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Zhang Z, Li L, Ge Y, Chen A, Diao S, Yang Y, Chen Q, Zhou Y, Shao J, Meng F, Yu L, Tian M, Qian X, Lin Z, Xie C, Liu B, Li R. Verteporfin-Mediated In Situ Nanovaccine Based on Local Conventional-Dose Hypofractionated Radiotherapy Enhances Antitumor and Immunomodulatory Effect. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2413387. [PMID: 40231790 DOI: 10.1002/advs.202413387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 03/06/2025] [Indexed: 04/16/2025]
Abstract
In situ radiotherapy is the most successful cytotoxic therapy available for the treatment of solid tumors, while high-dose radiotherapy per fraction is not yet widely and reliably used. To some extent, the major considerations of the disappointing results are on the risk of high-dose irradiation-induced damage to the surrounding normal tissues and the difficulty in distant metastasis control. To break these restraints, a gelatinase-responsive amphiphilic methoxypolyethyleneglycol-PVGLIG-polycaprolactone (mPEG-PVGLIG-PCL) nanoparticles' loading verteporfin (N@VP), a special photosensitizer that can also be excited by X-rays to produce cytotoxic singlet oxygen and greatly enhance radiotherapy efficacy, is prepared in this study. Herein, it is shown that the formed N@VP combined with conventional-dose radiation therapy (RT, 2 Gy (gray, a radiation dose unit)) can realize an antitumor effect no less than high-dose RT (8 Gy) and minimize radiation dose necessary to achieve local tumor control. Moreover, this radiosensitive nanosystem can exert excellent systemic antitumor immunity and abscopal effect, providing a preferable "in situ vaccine" strategy based on conventional-dose RT to achieve efficient systemic management of distant tumor metastasis. When combined with immunotherapy, this novel strategy for radiosensitization results in better immunotherapy sensitivity by stimulating significant immunogenic tumor cell death and synergistic antitumor immune responses.
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Affiliation(s)
- Zhifan Zhang
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Lin Li
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Yuchen Ge
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Anni Chen
- Nanjing International Hospital, Medical School of Nanjing University, Nanjing, 210019, China
| | - Shanchao Diao
- State Key Laboratory for Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Jiangsu Key Laboratory for Biosensors, Nanjing University of Posts & Telecommunications, Nanjing, 210023, China
| | - Yueling Yang
- Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Qianyue Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Yingling Zhou
- Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Jie Shao
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Fanyan Meng
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Lixia Yu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Manman Tian
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Xiaoping Qian
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Zhaoyu Lin
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Chen Xie
- State Key Laboratory for Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Jiangsu Key Laboratory for Biosensors, Nanjing University of Posts & Telecommunications, Nanjing, 210023, China
| | - Baorui Liu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Rutian Li
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
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2
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Guneri-Sozeri PY, Adebali O. Transcription factors, nucleotide excision repair, and cancer: A review of molecular interplay. Int J Biochem Cell Biol 2025; 179:106724. [PMID: 39672502 DOI: 10.1016/j.biocel.2024.106724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/05/2024] [Accepted: 12/07/2024] [Indexed: 12/15/2024]
Abstract
Bulky DNA adducts are mostly formed by external factors such as UV irradiation, smoking or treatment with DNA crosslinking agents. If such DNA adducts are not removed by nucleotide excision repair, they can lead to formation of driver mutations that contribute to cancer formation. Transcription factors (TFs) may critically affect both DNA adduct formation and repair efficiency at the binding site to DNA. For example, "hotspot" mutations in melanoma coincide with UV-induced accumulated cyclobutane pyrimidine dimer (CPD) adducts and/or inhibited repair at the binding sites of some TFs. Similarly, anticancer treatment with DNA cross-linkers may additionally generate DNA adducts leading to secondary mutations and the formation of malignant subclones. In addition, some TFs are overexpressed in response to UV irradiation or chemotherapeutic treatment, activating oncogenic and anti-oncogenic pathways independently of nucleotide excision repair itself. This review focuses on the interplay between TFs and nucleotide excision repair during cancer development and progression.
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Affiliation(s)
| | - Ogün Adebali
- Faculty of Engineering and Natural Sciences, Sabancı University, Istanbul 34956, Türkiye.
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3
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Chavez Varias D, Moon SH, Shin SH, Ryu BY. Selenium protects mouse spermatogonia against ivermectin-induced apoptosis by alleviating endoplasmic reticulum stress in vitro. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 287:117307. [PMID: 39520749 DOI: 10.1016/j.ecoenv.2024.117307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 10/21/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Ivermectin (IVM) is a widely used anthelmintic in human and veterinary medicine. However, the increasing use of IVM raises concerns about its potential harm against non-targeted organisms. This study demonstrates a novel mechanism where IVM triggers apoptosis via endoplasmic reticulum (ER) stress in GC-1 spg in vitro. The inhibitory effects of selenium (Se) against the toxicological mechanism were also explored. IVM dose-dependently induces oxidative stress, dysregulated Ca2+ levels, and intracellular protein aggregation. Increased mitochondria-associated ER membrane (MAM) activity through Glucose-regulated Protein 75 (Grp75) overloads the mitochondria with Ca2+, causing mitochondrial dysfunction. These simultaneous stressors lead to unfolded protein response and apoptosis. Se reverses all these subcellular events by promoting the expression of selenoprotein-encoding genes to maintain the ER and redox homeostasis. The testis-enriched Glutathione Peroxidase 4 (Gpx4) and the testis-specific Selenoprotein V (Selenov) are only upregulated in the IVM and Se co-treatment group, suggesting their potential role in stress response. These findings confirm that toxic doses of IVM lead to programmed cell death in type B spermatogonia through redox imbalance-associated ER stress. This study provides valuable insights into refining male reproductive toxicity evaluation, targeting of ER stress to protect male germ cells, and maintaining male fertility from IVM-induced toxicity.
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Affiliation(s)
- Daniel Chavez Varias
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do 17546, Republic of Korea
| | - Sung-Hwan Moon
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do 17546, Republic of Korea
| | - Seung Hee Shin
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do 17546, Republic of Korea
| | - Buom-Yong Ryu
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do 17546, Republic of Korea.
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4
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Shanmugam R, Majee P, Shi W, Ozturk MB, Vaiyapuri TS, Idzham K, Raju A, Shin SH, Fidan K, Low JL, Chua JY, Kong YC, Qi OY, Tan E, Chok AY, Seow-En I, Wee I, Macalinao DC, Chong DQ, Chang HY, Lee F, Leow WQ, Murata-Hori M, Xiaoqian Z, Shumei C, Tan CS, Dasgupta R, Tan IB, Tergaonkar V. Iron-(Fe3+)-Dependent Reactivation of Telomerase Drives Colorectal Cancers. Cancer Discov 2024; 14:1940-1963. [PMID: 38885349 PMCID: PMC11450372 DOI: 10.1158/2159-8290.cd-23-1379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 04/15/2024] [Accepted: 06/12/2024] [Indexed: 06/20/2024]
Abstract
Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with an increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by reactivating the dormant human telomerase reverse transcriptase (hTERT) subunit of the telomerase holoenzyme in an iron-(Fe3+)-dependent manner and thereby drives colorectal cancers. Chemical genetic screens combined with isothermal dose-response fingerprinting and mass spectrometry identified a small molecule SP2509 that specifically inhibits Pirin-mediated hTERT reactivation in colorectal cancers by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat and increased incidence of colorectal cancers. Small molecules like SP2509 represent a novel modality to target telomerase that acts as a driver of 90% of human cancers and is yet to be targeted in clinic. Significance: We show how iron-(Fe3+) in collusion with genetic factors reactivates telomerase, providing a molecular mechanism for the association between iron overload and increased incidence of colorectal cancers. Although no enzymatic inhibitors of telomerase have entered the clinic, we identify SP2509, a small molecule that targets telomerase reactivation and function in colorectal cancers.
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Affiliation(s)
- Raghuvaran Shanmugam
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Prativa Majee
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Wei Shi
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Mert B. Ozturk
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Thamil S. Vaiyapuri
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Khaireen Idzham
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Anandhkumar Raju
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Seung H. Shin
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Kerem Fidan
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Joo-Leng Low
- Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Singapore, Republic of Singapore.
| | - Joelle Y.H. Chua
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Yap C. Kong
- Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Singapore, Republic of Singapore.
| | - Ong Y. Qi
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
| | - Emile Tan
- Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
| | - Aik Y. Chok
- Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
| | - Isaac Seow-En
- Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
| | - Ian Wee
- Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
| | - Dominique C. Macalinao
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.
| | - Dawn Q. Chong
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.
| | - Hong Y. Chang
- Experimental Drug Development Center, Agency for Science, Technology, and Research (A*STAR), Singapore, Republic of Singapore.
| | - Fiona Lee
- Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Singapore, Republic of Singapore.
| | - Wei Q. Leow
- Department of Colorectal Surgery, Singapore General Hospital, Singapore, Republic of Singapore.
| | - Maki Murata-Hori
- Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Singapore, Republic of Singapore.
| | - Zhang Xiaoqian
- Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Singapore, Republic of Singapore.
| | - Chia Shumei
- Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Singapore, Republic of Singapore.
| | - Chris S.H. Tan
- Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, China.
| | - Ramanuj Dasgupta
- Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Singapore, Republic of Singapore.
| | - Iain B. Tan
- Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Singapore, Republic of Singapore.
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.
- Cancer and Stem Cell Biology, Duke-National University of Singapore, Singapore, Republic of Singapore.
| | - Vinay Tergaonkar
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Republic of Singapore.
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5
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Hirth A, Fatti E, Netz E, Acebron SP, Papageorgiou D, Švorinić A, Cruciat CM, Karaulanov E, Gopanenko A, Zhu T, Sinning I, Krijgsveld J, Kohlbacher O, Niehrs C. DEAD box RNA helicases are pervasive protein kinase interactors and activators. Genome Res 2024; 34:952-966. [PMID: 38986579 PMCID: PMC11293542 DOI: 10.1101/gr.278264.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 06/12/2024] [Indexed: 07/12/2024]
Abstract
DEAD box (DDX) RNA helicases are a large family of ATPases, many of which have unknown functions. There is emerging evidence that besides their role in RNA biology, DDX proteins may stimulate protein kinases. To investigate if protein kinase-DDX interaction is a more widespread phenomenon, we conducted three orthogonal large-scale screens, including proteomics analysis with 32 RNA helicases, protein array profiling, and kinome-wide in vitro kinase assays. We retrieved Ser/Thr protein kinases as prominent interactors of RNA helicases and report hundreds of binary interactions. We identified members of ten protein kinase families, which bind to, and are stimulated by, DDX proteins, including CDK, CK1, CK2, DYRK, MARK, NEK, PRKC, SRPK, STE7/MAP2K, and STE20/PAK family members. We identified MARK1 in all screens and validated that DDX proteins accelerate the MARK1 catalytic rate. These findings indicate pervasive interactions between protein kinases and DEAD box RNA helicases, and provide a rich resource to explore their regulatory relationships.
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Affiliation(s)
- Alexander Hirth
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany
- Faculty of Biosciences, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany
| | - Edoardo Fatti
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany
- Faculty of Biosciences, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany
| | - Eugen Netz
- Applied Bioinformatics, Department of Computer Science, University of Tübingen, 72076 Tübingen, Germany
- Institute for Bioinformatics and Medical Informatics, University of Tübingen, 72076 Tübingen, Germany
| | - Sergio P Acebron
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany
| | - Dimitris Papageorgiou
- Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany
| | - Andrea Švorinić
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany
- Faculty of Biosciences, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany
- Heidelberg University Biochemistry Center (BZH), 69120 Heidelberg, Germany
| | - Cristina-Maria Cruciat
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany
| | | | | | - Tianheng Zhu
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany
- Faculty of Biosciences, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany
| | - Irmgard Sinning
- Heidelberg University Biochemistry Center (BZH), 69120 Heidelberg, Germany
| | - Jeroen Krijgsveld
- Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany
| | - Oliver Kohlbacher
- Applied Bioinformatics, Department of Computer Science, University of Tübingen, 72076 Tübingen, Germany
- Institute for Bioinformatics and Medical Informatics, University of Tübingen, 72076 Tübingen, Germany
- Translational Bioinformatics, University Hospital Tübingen, 72076 Tübingen, Germany
| | - Christof Niehrs
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany;
- Institute of Molecular Biology (IMB), 55128 Mainz, Germany
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6
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Kim SM, Han GU, Kim SG, Moon SH, Shin SH, Ryu BY. Mitigation of benzyl butyl phthalate toxicity in male germ cells with combined treatment of parthenolide, N-acetylcysteine, and 3-methyladenine. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 280:116544. [PMID: 38838463 DOI: 10.1016/j.ecoenv.2024.116544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 04/09/2024] [Accepted: 06/01/2024] [Indexed: 06/07/2024]
Abstract
Benzyl butyl phthalate (BBP) is a widely used plasticizer that poses various potential health hazards. Although BBP has been extensively studied, the direct mechanism underlying its toxicity in male germ cells remains unclear. Therefore, we investigated BBP-mediated male germ cell toxicity in GC-1 spermatogonia (spg), a differentiated mouse male germ cell line. This study investigated the impact of BBP on reactive oxygen species (ROS) generation, apoptosis, and autophagy regulation, as well as potential protective measures against BBP-induced toxicity. A marked dose-dependent decrease in GC-1 spg cell proliferation was observed following treatment with BBP at 12.5 μM. Exposure to 50 μM BBP, approximating the IC50 of 53.9 μM, markedly increased cellular ROS generation and instigated apoptosis, as evidenced by augmented protein levels of both intrinsic and extrinsic apoptosis-related markers. An amount of 50 μM BBP induced marked upregulation of autophagy regulator proteins, p38 MAPK, and extracellular signal-regulated kinase and substantially downregulated the phosphorylation of key kinases involved in regulating cell proliferation, including phosphoinositide 3-kinase, protein kinase B, mammalian target of rapamycin (mTOR), c-Jun N-terminal kinase. The triple combination of N-acetylcysteine, parthenolide, and 3-methyladenine markedly restored cell proliferation, decreased BBP-induced apoptosis and autophagy, and restored mTOR phosphorylation. This study provides new insights into BBP-induced male germ cell toxicity and highlights the therapeutic potential of the triple inhibitors in mitigating BBP toxicity.
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Affiliation(s)
- Seok-Man Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea
| | - Gil Un Han
- Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea
| | - Seul Gi Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea
| | - Sung-Hwan Moon
- Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea
| | - Seung Hee Shin
- Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea
| | - Buom-Yong Ryu
- Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do, 17546, Republic of Korea.
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7
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Kim SM, Kim YH, Han GU, Kim SG, Kim BJ, Moon SH, Shin SH, Ryu BY. Elucidating the mechanisms and mitigation strategies for six-phthalate-induced toxicity in male germ cells. Front Cell Dev Biol 2024; 12:1398176. [PMID: 39050888 PMCID: PMC11266291 DOI: 10.3389/fcell.2024.1398176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 06/18/2024] [Indexed: 07/27/2024] Open
Abstract
Phthalate esters (PAEs) are primary plasticizers and endocrine-disrupting chemicals (EDCs) that are extensively used in numerous everyday consumer products. Although the adverse effects of single PAEs have been studied, our understanding of the effect of multiple phthalate exposure on male germ cell vitality remains limited. Therefore, this study aimed to investigate the collective effects of a mixture of PAEs (MP) comprising diethyl-, bis (2-ethylhexyl)-, dibutyl-, diisononyl-, diisobutyl-, and benzyl butyl-phthalates in the proportions of 35, 21, 15, 15, 8, and 5%, respectively, on differentiated male germ cells using GC-1 spermatogonia (spg) cells. As a mixture, MP substantially hindered GC-1 spg cell proliferation at 3.13 μg/mL, with a half-maximal inhibitory concentration of 16.9 μg/mL. Treatment with 25 μg/mL MP significantly induced reactive oxygen species generation and promoted apoptosis. Furthermore, MP activated autophagy and suppressed phosphorylation of phosphoinositide 3-kinase, protein kinase B, and mammalian target of rapamycin (mTOR). The triple inhibitor combination treatment comprising parthenolide, N-acetylcysteine, and 3-methyladenine effectively reversed MP-induced GC-1 spg cell proliferation inhibition, mitigated apoptosis and autophagy, and restored mTOR phosphorylation. This study is the first to elucidate the mechanism underlying MP-induced male germ cell toxicity and the restoration of male germ cell proliferation mediated by chemical inhibitors. Therefore, it provides valuable insights into the existing literature by proposing a combinatorial toxicity mitigation strategy to counteract male germ cell toxicity induced by various EDCs exposure.
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Affiliation(s)
- Seok-Man Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, Republic of Korea
| | - Yong-Hee Kim
- AttisLab Inc., Anyang-Si, Gyeonggi-Do, Republic of Korea
| | - Gil Un Han
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, Republic of Korea
| | - Seul Gi Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, Republic of Korea
| | - Bang-Jin Kim
- Department of Surgery, Division of Surgical Sciences, Columbia University Irving Medical Center, New York, NY, United States
| | - Sung-Hwan Moon
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, Republic of Korea
| | - Seung Hee Shin
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, Republic of Korea
| | - Buom-Yong Ryu
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, Republic of Korea
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8
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Gu HJ, Kim DY, Shin SH, Rahman MS, Lee HS, Pang MG, Kim JM, Ryu BY. Genome-wide transcriptome analysis reveals that Bisphenol A activates immune responses in skeletal muscle. ENVIRONMENTAL RESEARCH 2024; 252:119034. [PMID: 38701888 DOI: 10.1016/j.envres.2024.119034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 03/31/2024] [Accepted: 04/25/2024] [Indexed: 05/05/2024]
Abstract
Cumulative human exposure to the environmental toxin, bisphenol A (BPA), has raised important health concerns in recent decades. However, the direct genomic regulation of BPA in skeletal muscles and its clinical significance are poorly understood. Therefore, we conducted a genome-wide transcriptome analysis after daily oral administration of BPA at the lowest observed adverse-effect level (LOAEL, 50 mg/kg) in male mice for six weeks to explore the gene-expression regulations in skeletal muscle induced by BPA. The primary Gene Ontology terms linked to BPA-dependent, differentially expressed genes at LOAEL comprised adaptive-immune response, positive regulation of T cell activation, and immune system process. The gene-set enrichment analysis disclosed increased complement-associated genes [complement components 3 (C3) and 4B, complement factor D, complement receptor 2, and immunoglobulin lambda constant 2] in the group administered with BPA, with a false-discovery rate of <0.05. Subsequent validation analysis conducted in BPA-fed animal skeletal muscle tissue and in vitro experiments confirmed that BPA induced immune activation, as evidenced by increased levels of C3 and C4α proteins in mice, C2C12 myoblasts, and mouse skeletal muscle cells. In addition, BPA markedly upregulated the transcription of tumor necrosis factor-α (Tnfα) in C2C12 myoblasts and mouse skeletal muscle cells, which was substantially inhibited by 5z-7-oxozeanol and parthenolide, providing further evidence of BPA-induced inflammation in muscle cells. Our bioinformatics and subsequent animal and in vitro validations demonstrate that BPA can activate inflammation in skeletal muscle, which could be a risk factor underlying chronic muscle weakness and wastage.
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Affiliation(s)
- Hyo Jin Gu
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Do-Young Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Seung Hee Shin
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Md Saidur Rahman
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Hee-Seok Lee
- Department of Food Science and Biotechnology, Chung-Ang University, Anseong, 17546, Republic of Korea; Department of Food Safety and Regulatory Science, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Myung-Geol Pang
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea
| | - Jun-Mo Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea.
| | - Buom-Yong Ryu
- Department of Animal Science and Technology, Chung-Ang University, Anseong, 17546, Republic of Korea.
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9
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Kim SG, Jeon JH, Shin SH, Varias DC, Moon SH, Ryu BY. Inhibition of reactive oxygen species generation by N-Acetyl Cysteine can mitigate male germ cell toxicity induced by bisphenol analogs. Food Chem Toxicol 2024; 188:114652. [PMID: 38583502 DOI: 10.1016/j.fct.2024.114652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/25/2024] [Accepted: 04/04/2024] [Indexed: 04/09/2024]
Abstract
The estrogen-like effect of bisphenol A (BPA) disrupting the maintenance of functional male germ cells is associated with male sub-fertility. This study investigated toxicity of male germ cells induced by four bisphenol analogs: BPA, BPAF, BPF, and BPS. The investigation of bisphenol analogs' impact on male germ cells included assessing proliferation, apoptosis induction, and the capacity to generate reactive oxygen species (ROS) in GC-1 spermatogonia (spg) cells, specifically type B spermatogonia. Additionally, the therapeutic potential and protective effects of N-Acetyl Cysteine (NAC) and NF-κB inhibitor parthenolide was evaluated. In comparison to BPA, BPF and BPS, BPAF exhibited the most pronounced adverse effect in GC-1 spg cell proliferation. This effect was characterized by pronounced inhibition of phosphorylation of PI3K, AKT, and mTOR, along with increased release of cytochrome c and subsequent cleavages of caspase 3, caspase 7, and poly (ADP-ribose) polymerase. Both NAC and parthenolide were effective reducing cellular ROS induced by BPAF. However, only NAC demonstrated a substantial recovery in proliferation, accompanied by a significant reduction in cytochrome c release and cleaved PARP. These results suggest that NAC supplementation may play an effective therapeutic role in countering germ cell toxicity induced by environmental pollutants with robust oxidative stress-generating capacity.
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Affiliation(s)
- Seul Gi Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Jeong Hoon Jeon
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Seung Hee Shin
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Daniel Chavez Varias
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Sung-Hwan Moon
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Buom-Yong Ryu
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
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10
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Guo Q, Jin Y, Chen X, Ye X, Shen X, Lin M, Zeng C, Zhou T, Zhang J. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther 2024; 9:53. [PMID: 38433280 PMCID: PMC10910037 DOI: 10.1038/s41392-024-01757-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 03/05/2024] Open
Abstract
NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.
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Affiliation(s)
- Qing Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yizi Jin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xinyu Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, PR China
| | - Xiaomin Ye
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Xin Shen
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingxi Lin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cheng Zeng
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Teng Zhou
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jian Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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11
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Kim SM, Kim YH, Han GU, Kim SG, Bhang DH, Kim BG, Moon SH, Shin SH, Ryu BY. Diisobutyl phthalate (DiBP)-induced male germ cell toxicity and its alleviation approach. Food Chem Toxicol 2024; 184:114387. [PMID: 38123059 DOI: 10.1016/j.fct.2023.114387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/22/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023]
Abstract
Diisobutyl phthalate (DiBP) is a commonly used plasticizer in manufacturing consumer and industrial products to improve flexibility and durability. Despite of the numerous studies, however, the direct mechanism underlying the male reproductive damage of DiBP is poorly understood. In this study, we investigated the male germ cell toxicity of DiBP using GC-1 spermatogonia (spg) cells. Our results indicated that DiBP exposure causes oxidative stress and apoptosis in GC-1 spg cells. In addition, DiBP-derived autophagy activation and down-regulation of phosphoinositide 3-kinase (PI3K)-AKT and extracellular signal-regulated kinase (ERK) pathways further inhibited GC-1 spg cell proliferation, indicating that DiBP can instigate male germ cell toxicity by targeting several pathways. Importantly, a combined treatment of parthenolide, N-acetylcysteine, and 3-methyladenine significantly reduced DiBP-induced male germ cell toxicity and restored proliferation. Taken together, the results of this study can provide valuable information to the existing literature by enhancing the understanding of single phthalate DiBP-derived male germ cell toxicity and the therapeutic interventions that can mitigate DiBP damage.
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Affiliation(s)
- Seok-Man Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Yong-Hee Kim
- AttisLab Inc., Anyang, Gyeonggi-Do, 14059, Republic of Korea.
| | - Gil Un Han
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Seul Gi Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Dong Ha Bhang
- AttisLab Inc., Anyang, Gyeonggi-Do, 14059, Republic of Korea.
| | - Byung-Gak Kim
- Biattic Inc., Anyang, Gyeonggi-Do, 14059, Republic of Korea.
| | - Sung-Hwan Moon
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Seung Hee Shin
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Buom-Yong Ryu
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
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12
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He L, Yang J, Hao Y, Yang X, Shi X, Zhang D, Zhao D, Yan W, Bie X, Chen L, Chen G, Zhao S, Liu X, Zheng H, Zhang K. DDX20: A Multifunctional Complex Protein. Molecules 2023; 28:7198. [PMID: 37894677 PMCID: PMC10608988 DOI: 10.3390/molecules28207198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/18/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
DEAD-box decapping enzyme 20 (DDX20) is a putative RNA-decapping enzyme that can be identified by the conserved motif Asp-Glu-Ala-Asp (DEAD). Cellular processes involve numerous RNA secondary structure alterations, including translation initiation, nuclear and mitochondrial splicing, and assembly of ribosomes and spliceosomes. DDX20 reportedly plays an important role in cellular transcription and post-transcriptional modifications. On the one hand, DDX20 can interact with various transcription factors and repress the transcriptional process. On the other hand, DDX20 forms the survival motor neuron complex and participates in the assembly of snRNP, ultimately affecting the RNA splicing process. Finally, DDX20 can potentially rely on its RNA-unwinding enzyme function to participate in microRNA (miRNA) maturation and act as a component of the RNA-induced silencing complex. In addition, although DDX20 is not a key component in the innate immune system signaling pathway, it can affect the nuclear factor kappa B (NF-κB) and p53 signaling pathways. In particular, DDX20 plays different roles in tumorigenesis development through the NF-κB signaling pathway. This process is regulated by various factors such as miRNA. DDX20 can influence processes such as viral replication in cells by interacting with two proteins in Epstein-Barr virus and can regulate the replication process of several viruses through the innate immune system, indicating that DDX20 plays an important role in the innate immune system. Herein, we review the effects of DDX20 on the innate immune system and its role in transcriptional and post-transcriptional modification processes, based on which we provide an outlook on the future of DDX20 research in innate immunity and viral infections.
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Affiliation(s)
- Lu He
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Jinke Yang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Yu Hao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Xing Yang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Xijuan Shi
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Dajun Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Dengshuai Zhao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Wenqian Yan
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Xintian Bie
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Lingling Chen
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Guohui Chen
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Siyue Zhao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Xiangtao Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Haixue Zheng
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Keshan Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
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13
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Wang G, He X, Dai H, Lin L, Cao W, Fu Y, Diao W, Ding M, Zhang Q, Chen W, Guo H. WDR4 promotes the progression and lymphatic metastasis of bladder cancer via transcriptional down-regulation of ARRB2. Oncogenesis 2023; 12:47. [PMID: 37783676 PMCID: PMC10545698 DOI: 10.1038/s41389-023-00493-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 09/17/2023] [Accepted: 09/20/2023] [Indexed: 10/04/2023] Open
Abstract
Lymph node (LN) metastasis is one of the key prognostic factors in bladder cancer, but its underlying mechanisms remain unclear. Here, we found that elevated expression of WD repeat domain 4 (WDR4) in bladder cancer correlated with worse prognosis. WDR4 can promote the LN metastasis and proliferation of bladder cancer cells. Mechanistic studies showed that WDR4 can promote the nuclear localization of DEAD-box helicase 20 (DDX20) and act as an adaptor to bind DDX20 and Early growth response 1 (Egr1), thereby inhibiting Egr1-promoted transcriptional expression of arrestin beta 2 (ARRB2) and ultimately contributing to the progression of bladder cancer. Immunohistochemical analysis confirmed that WDR4 expression is also an independent predictor of LN metastasis in bladder cancer. Our results reveal a novel mechanism of LN metastasis and progression in bladder cancer and identify WDR4 as a potential therapeutic target for metastatic bladder cancer.
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Affiliation(s)
- Guoli Wang
- Department of Urology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, 210008, China
| | - Xin He
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, 210008, China
| | - Huiqi Dai
- Department of Urology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, 210008, China
| | - Lingyi Lin
- Department of Urology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, 210008, China
| | - Wenmin Cao
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, 210008, China
| | - Yao Fu
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Wenli Diao
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, 210008, China
| | - Meng Ding
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, 210008, China
| | - Qing Zhang
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, 210008, China.
| | - Wei Chen
- Department of Urology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China.
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, 210008, China.
| | - Hongqian Guo
- Department of Urology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China.
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, 210008, China.
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14
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Ang HL, Mohan CD, Shanmugam MK, Leong HC, Makvandi P, Rangappa KS, Bishayee A, Kumar AP, Sethi G. Mechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds. Med Res Rev 2023. [PMID: 36929669 DOI: 10.1002/med.21948] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 12/19/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is a complex process with a primordial role in cellular transformation whereby an epithelial cell transforms and acquires a mesenchymal phenotype. This transformation plays a pivotal role in tumor progression and self-renewal, and exacerbates resistance to apoptosis and chemotherapy. EMT can be initiated and promoted by deregulated oncogenic signaling pathways, hypoxia, and cells in the tumor microenvironment, resulting in a loss-of-epithelial cell polarity, cell-cell adhesion, and enhanced invasive/migratory properties. Numerous transcriptional regulators, such as Snail, Slug, Twist, and ZEB1/ZEB2 induce EMT through the downregulation of epithelial markers and gain-of-expression of the mesenchymal markers. Additionally, signaling cascades such as Wnt/β-catenin, Notch, Sonic hedgehog, nuclear factor kappa B, receptor tyrosine kinases, PI3K/AKT/mTOR, Hippo, and transforming growth factor-β pathways regulate EMT whereas they are often deregulated in cancers leading to aberrant EMT. Furthermore, noncoding RNAs, tumor-derived exosomes, and epigenetic alterations are also involved in the modulation of EMT. Therefore, the regulation of EMT is a vital strategy to control the aggressive metastatic characteristics of tumor cells. Despite the vast amount of preclinical data on EMT in cancer progression, there is a lack of clinical translation at the therapeutic level. In this review, we have discussed thoroughly the role of the aforementioned transcription factors, noncoding RNAs (microRNAs, long noncoding RNA, circular RNA), signaling pathways, epigenetic modifications, and tumor-derived exosomes in the regulation of EMT in cancers. We have also emphasized the contribution of EMT to drug resistance and possible therapeutic interventions using plant-derived natural products, their semi-synthetic derivatives, and nano-formulations that are described as promising EMT blockers.
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Affiliation(s)
- Hui Li Ang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Hin Chong Leong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Pooyan Makvandi
- Istituto Italiano di Tecnologia Centre for Materials Interface, Pontedera, Pisa, Italy
| | | | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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15
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Arna AB, Patel H, Singh RS, Vizeacoumar FS, Kusalik A, Freywald A, Vizeacoumar FJ, Wu Y. Synthetic lethal interactions of DEAD/H-box helicases as targets for cancer therapy. Front Oncol 2023; 12:1087989. [PMID: 36761420 PMCID: PMC9905851 DOI: 10.3389/fonc.2022.1087989] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/28/2022] [Indexed: 01/26/2023] Open
Abstract
DEAD/H-box helicases are implicated in virtually every aspect of RNA metabolism, including transcription, pre-mRNA splicing, ribosomes biogenesis, nuclear export, translation initiation, RNA degradation, and mRNA editing. Most of these helicases are upregulated in various cancers and mutations in some of them are associated with several malignancies. Lately, synthetic lethality (SL) and synthetic dosage lethality (SDL) approaches, where genetic interactions of cancer-related genes are exploited as therapeutic targets, are emerging as a leading area of cancer research. Several DEAD/H-box helicases, including DDX3, DDX9 (Dbp9), DDX10 (Dbp4), DDX11 (ChlR1), and DDX41 (Sacy-1), have been subjected to SL analyses in humans and different model organisms. It remains to be explored whether SDL can be utilized to identity druggable targets in DEAD/H-box helicase overexpressing cancers. In this review, we analyze gene expression data of a subset of DEAD/H-box helicases in multiple cancer types and discuss how their SL/SDL interactions can be used for therapeutic purposes. We also summarize the latest developments in clinical applications, apart from discussing some of the challenges in drug discovery in the context of targeting DEAD/H-box helicases.
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Affiliation(s)
- Ananna Bhadra Arna
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Hardikkumar Patel
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Ravi Shankar Singh
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Frederick S. Vizeacoumar
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Anthony Kusalik
- Department of Computer Science, University of Saskatchewan, Saskatoon, SK, Canada
| | - Andrew Freywald
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Franco J. Vizeacoumar
- Division of Oncology, College of Medicine, University of Saskatchewan and Saskatchewan Cancer Agency, Saskatoon, SK, Canada,*Correspondence: Yuliang Wu, ; Franco J. Vizeacoumar,
| | - Yuliang Wu
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada,*Correspondence: Yuliang Wu, ; Franco J. Vizeacoumar,
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16
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Kumar S, Mathew SO, Aharwal RP, Tulli HS, Mohan CD, Sethi G, Ahn KS, Webber K, Sandhu SS, Bishayee A. Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal. Pharmaceuticals (Basel) 2023; 16:160. [PMID: 37259311 PMCID: PMC9966696 DOI: 10.3390/ph16020160] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 08/04/2023] Open
Abstract
Cancer represents the second most deadly disease and one of the most important public health concerns worldwide. Surgery, chemotherapy, radiation therapy, and immune therapy are the major types of treatment strategies that have been implemented in cancer treatment. Unfortunately, these treatment options suffer from major limitations, such as drug-resistance and adverse effects, which may eventually result in disease recurrence. Many phytochemicals have been investigated for their antitumor efficacy in preclinical models and clinical studies to discover newer therapeutic agents with fewer adverse effects. Withaferin A, a natural bioactive molecule isolated from the Indian medicinal plant Withania somnifera (L.) Dunal, has been reported to impart anticancer activities against various cancer cell lines and preclinical cancer models by modulating the expression and activity of different oncogenic proteins. In this article, we have comprehensively discussed the biosynthesis of withaferin A as well as its antineoplastic activities and mode-of-action in in vitro and in vivo settings. We have also reviewed the effect of withaferin A on the expression of miRNAs, its combinational effect with other cytotoxic agents, withaferin A-based formulations, safety and toxicity profiles, and its clinical potential.
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Affiliation(s)
- Suneel Kumar
- Bio-Design Innovation Centre, Rani Durgavati University, Jabalpur 482 001, India
| | - Stephen O. Mathew
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | | | - Hardeep Singh Tulli
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133 207, India
| | | | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Kwang-Seok Ahn
- Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kassidy Webber
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Sardul Singh Sandhu
- Bio-Design Innovation Centre, Rani Durgavati University, Jabalpur 482 001, India
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
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Sandhu SS, Rouz SK, Kumar S, Swamy N, Deshmukh L, Hussain A, Haque S, Tuli HS. Ursolic acid: a pentacyclic triterpenoid that exhibits anticancer therapeutic potential by modulating multiple oncogenic targets. Biotechnol Genet Eng Rev 2023:1-31. [PMID: 36600517 DOI: 10.1080/02648725.2022.2162257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 12/20/2022] [Indexed: 01/06/2023]
Abstract
The world is currently facing a global challenge against neoplastic diseases. Chemotherapy, hormonal therapy, surgery, and radiation therapy are some approaches used to treat cancer. However, these treatments are frequently causing side effects in patients, such as multidrug resistance, fever, weakness, and allergy, among others side effects. As a result, current research has focused on phytochemical compounds isolated from plants to treat deadly cancers. Plants are excellent resources of bioactive molecules, and many natural molecules have exceptional anticancer properties. They produce diverse anticancer derivatives such as alkaloids, terpenoids, flavonoids, pigments, and tannins, which have powerful anticancer activities against various cancer cell lines and animal models. Because of their safety, eco-friendly, and cost-effective nature, research communities have recently focused on various phytochemical bioactive molecules. Ursolic acid (UA) and its derivative compounds have anti-inflammatory, anticancer, apoptosis induction, anti-carcinogenic, and anti-breast cancer proliferation properties. Ursolic acid (UA) can improve the clinical management of human cancer because it inhibits cancer cell viability and proliferation, preventing tumour angiogenesis and metastatic activity. Therefore, the present article focuses on numerous bioactivities of Ursolic acid (UA), which can inhibit cancer cell production, mechanism of action, and modulation of anticancer properties via regulating various cellular processes.
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Affiliation(s)
| | - Sharareh Khorami Rouz
- School of Life Sciences, Manipal Academy of Higher Education, Dubai, United Arab Emirates
| | - Suneel Kumar
- Bio-Design Innovation Centre, Rani Durgavati University, Jabalpur, India
| | - Nitin Swamy
- Fungal Biotechnology and Invertebrate Pathology Laboratory Department of Biological Sciences, Rani Durgavati University, Jabalpur, India
| | - Loknath Deshmukh
- School of Life and Allied Science, ITM University, Raipur, India
| | - Arif Hussain
- School of Life Sciences, Manipal Academy of Higher Education, Dubai, United Arab Emirates
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Arabia and Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
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Miralles MP, Sansa A, Beltran M, Soler RM, Garcera A. Survival motor neuron protein and neurite degeneration are regulated by Gemin3 in spinal muscular atrophy motoneurons. Front Cell Neurosci 2022; 16:1054270. [PMID: 36619669 PMCID: PMC9813745 DOI: 10.3389/fncel.2022.1054270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder caused by reduction of the ubiquitously expressed protein Survival Motor Neuron (SMN). Low levels of SMN impact on spinal cord motoneurons (MNs) causing their degeneration and progressive muscle weakness and atrophy. To study the molecular mechanisms leading to cell loss in SMN-reduced MNs, we analyzed the NF-κB intracellular pathway in SMA models. NF-κB pathway activation is required for survival and regulates SMN levels in cultured MNs. Here we describe that NF-κB members, inhibitor of kappa B kinase beta (IKKβ), and RelA, were reduced in SMA mouse and human MNs. In addition, we observed that Gemin3 protein level was decreased in SMA MNs, but not in non-neuronal SMA cells. Gemin3 is a core member of the SMN complex responsible for small nuclear ribonucleoprotein biogenesis, and it regulates NF-κB activation through the mitogen-activated protein kinase TAK1. Our experiments showed that Gemin3 knockdown reduced SMN, IKKβ, and RelA protein levels, and caused significant neurite degeneration. Overexpression of SMN increased Gemin3 protein in SMA MNs, but did not prevent neurite degeneration in Gemin3 knockdown cells. These data indicated that Gemin3 reduction may contribute to cell degeneration in SMA MNs.
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Importance of TAK-1 levels in patients with non-small cell lung carcinoma. TURK GOGUS KALP DAMAR CERRAHISI DERGISI 2022; 30:574-583. [PMID: 36605324 PMCID: PMC9801478 DOI: 10.5606/tgkdc.dergisi.2022.21975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 09/03/2021] [Indexed: 01/07/2023]
Abstract
Background In this study, we aimed to investigate the relationship between survival, tumor dimension, grade and stage in respect to transforming growth factor-β-activating kinase (TAK-1) extensity, severity and total score in patients undergoing resection for Stage 1B-2B non-small cell lung cancer. Methods Between January 2000 and December 2014, a total of 70 patients (64 males, 6 females; mean age: 63.4+9.6 years; range, 32 to 78 years) who underwent surgery with resectable non-small cell lung cancer in Stage 1-2b were included. The patients were divided into two groups as Group 1 (n=35) consisting of patients with squamous cell carcinoma and Group 2 (n=35) consisting of patients with adenocarcinoma. The control group consisted of 20 patients (Group 3) who underwent surgery due to non-cancer causes. The relationship between TAK-1 staining (extensity, severity, total scores) and grade, survival time, T factor, N factor, and chemotherapy administration was examined. Pathology specimens of the patients were evaluated for the degree of staining with TAK-1 primary antibody. Results There was a strong correlation between the tumor grade and TAK-1 primary antibody staining level, independently from histopathological type. A significant correlation was found between dimension, stage, and TAK-1 staining in patients with squamous cell carcinoma. No statistically significant difference was found in the other factors, except for grade factor, in patients with adenocarcinoma. Conclusion The current study provides precious information about the effects of TAK-1, in clinicopathological behavior and survival of malignant cells, particularly in common histopathological types of lung cancer. We believe that our data can be useful, particularly in evaluating the response to targeted therapies and the prognosis of the disease.
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20
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A Macrophage Differentiation-Mediated Gene: DDX20 as a Molecular Biomarker Encompassing the Tumor Microenvironment, Disease Staging, and Prognoses in Hepatocellular Carcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9971776. [PMID: 36246406 PMCID: PMC9556188 DOI: 10.1155/2022/9971776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/03/2022] [Accepted: 09/17/2022] [Indexed: 11/18/2022]
Abstract
Background DDX20 involves the mechanism of cell proliferate, mitogenic Ets transcriptional suppressor (METS), which can arrest the cell cycle of macrophages. However, little is known about DDX20 expression, clinical values, and the relationship with tumor microenvironment in HCC. Methods We mined the transcriptional, protein expression and survival data of DDX20 in HCC from online databases. The immunological effects of DDX20 were estimated by bioinformatic algorithms. The RNAi and CRISPR screening were used to assess the gene effect of DDX20 for the EGFR gene in liver tumor cell. Results We found that the DDX20 was highly expressed in HCC. The qRT-PCR result shows a significantly upregulated DDX20 expression in HCC samples from the West China Hospital. The high mRNA expression of DDX20 is associated with a poor survival. DDX20 expression is positively correlated with MDSCs in HCC tissues. Moreover, DDX20 has a high predicted ability for the response to immunotherapy. Furthermore, hsa-mir-324-5p could regulate the macrophage differentiation by interacting with DDX20. Meanwhile, the EGFR gene gets a high dependency score for DDX20. Conclusion In sum, DDX20 may serve as a prognostic marker for worse clinical outcomes with HCC and potentially enable more precise and personalized immunotherapeutic strategies in the future.
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Bizen N, Bepari AK, Zhou L, Abe M, Sakimura K, Ono K, Takebayashi H. Ddx20, an Olig2 binding factor, governs the survival of neural and oligodendrocyte progenitor cells via proper Mdm2 splicing and p53 suppression. Cell Death Differ 2022; 29:1028-1041. [PMID: 34974536 PMCID: PMC9090832 DOI: 10.1038/s41418-021-00915-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/05/2021] [Accepted: 09/20/2021] [Indexed: 12/13/2022] Open
Abstract
Olig2 is indispensable for motoneuron and oligodendrocyte fate-specification in the pMN domain of embryonic spinal cords, and also involved in the proliferation and differentiation of several cell types in the nervous system, including neural progenitor cells (NPCs) and oligodendrocytes. However, how Olig2 controls these diverse biological processes remains unclear. Here, we demonstrated that a novel Olig2-binding protein, DEAD-box helicase 20 (Ddx20), is indispensable for the survival of NPCs and oligodendrocyte progenitor cells (OPCs). A central nervous system (CNS)-specific Ddx20 conditional knockout (cKO) demonstrated apoptosis and cell cycle arrest in NPCs and OPCs, through the potentiation of the p53 pathway in DNA damage-dependent and independent manners, including SMN complex disruption and the abnormal splicing of Mdm2 mRNA. Analyzes of Olig2 null NPCs showed that Olig2 contributed to NPC proliferation through Ddx20 protein stabilization. Our findings provide novel mechanisms underlying the Olig2-mediated proliferation of NPCs, via the Ddx20-p53 axis, in the embryonic CNS.
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Affiliation(s)
- Norihisa Bizen
- Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Asim K Bepari
- Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.,Department of Pharmaceutical Sciences, North South University, Dhaka, Bangladesh
| | - Li Zhou
- Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.,Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.,Center for Coordination of Research Facilities (CCRF), Niigata University, Niigata, Japan
| | - Manabu Abe
- Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.,Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Japan
| | - Kenji Sakimura
- Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.,Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Japan
| | - Katsuhiko Ono
- Developmental Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hirohide Takebayashi
- Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan. .,Center for Coordination of Research Facilities (CCRF), Niigata University, Niigata, Japan.
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22
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Guimarães‐Teixeira C, Lobo J, Miranda‐Gonçalves V, Barros‐Silva D, Martins‐Lima C, Monteiro‐Reis S, Sequeira JP, Carneiro I, Correia MP, Henrique R, Jerónimo C. Downregulation of m 6 A writer complex member METTL14 in bladder urothelial carcinoma suppresses tumor aggressiveness. Mol Oncol 2022; 16:1841-1856. [PMID: 35048498 PMCID: PMC9067151 DOI: 10.1002/1878-0261.13181] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/06/2021] [Accepted: 01/17/2022] [Indexed: 11/08/2022] Open
Abstract
N6-methyladenosine (m6 A) and its regulatory proteins have been associated with tumorigenesis in several cancer types. However, knowledge on the mechanistic network related to m6 A in bladder cancer (BlCa) is rather limited, requiring further investigation of its functional role. We aimed to uncover the biological role of m6 A and related proteins in BlCa and understand how this influences tumor aggressiveness. N6-adenosine-methyltransferase catalytic subunit (METTL3), N6-adenosine-methyltransferase noncatalytic subunit (METTL14), protein virilizer homolog (VIRMA), and RNA demethylase ALKBH5 (ALKBH5) had significantly lower expression levels in BlCa compared to that in normal urothelium. METTL14 knockdown led to disruption of the remaining methyltransferase complex and a decrease in m6 A abundance, as well as overall reduced tumor aggressiveness (decreased cell invasion and migration capacity and increased apoptosis). Furthermore, in vivo, METTL14 knockdown caused tumor size reduction. Collectively, we propose methyltransferase METTL14 as a key component for m6 A RNA deposit and that it is closely related to BlCa progression, playing an important role in tumor aggressiveness. These data contribute to a better understanding of the m6 A writer complex, which might constitute an appealing therapeutic target.
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Affiliation(s)
- Catarina Guimarães‐Teixeira
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
- PhD Programme in Pathology & Molecular GeneticsSchool of Medicine & Biomedical Sciences–University of Porto (ICBAS‐UP)Portugal
| | - João Lobo
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
- PhD Programme in Pathology & Molecular GeneticsSchool of Medicine & Biomedical Sciences–University of Porto (ICBAS‐UP)Portugal
- Department of PathologyPortuguese Oncology Institute of Porto (IPOP)Portugal
- Department of Pathology and Molecular ImmunologySchool of Medicine & Biomedical Sciences–University of Porto (ICBAS‐UP)Portugal
| | - Vera Miranda‐Gonçalves
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
- Department of Pathology and Molecular ImmunologySchool of Medicine & Biomedical Sciences–University of Porto (ICBAS‐UP)Portugal
| | - Daniela Barros‐Silva
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
- PhD Programme in Pathology & Molecular GeneticsSchool of Medicine & Biomedical Sciences–University of Porto (ICBAS‐UP)Portugal
| | - Cláudia Martins‐Lima
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
| | - Sara Monteiro‐Reis
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
| | - José Pedro Sequeira
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
| | - Isa Carneiro
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
- Department of PathologyPortuguese Oncology Institute of Porto (IPOP)Portugal
| | - Margareta P. Correia
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
- Department of Pathology and Molecular ImmunologySchool of Medicine & Biomedical Sciences–University of Porto (ICBAS‐UP)Portugal
| | - Rui Henrique
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
- Department of PathologyPortuguese Oncology Institute of Porto (IPOP)Portugal
- Department of Pathology and Molecular ImmunologySchool of Medicine & Biomedical Sciences–University of Porto (ICBAS‐UP)Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics GroupResearch Center of IPO Porto (CI‐IPOP)/RISE@CI‐IPOP (Health Research Network)Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC)Portugal
- Department of Pathology and Molecular ImmunologySchool of Medicine & Biomedical Sciences–University of Porto (ICBAS‐UP)Portugal
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Aggarwal V, Tuli HS, Tania M, Srivastava S, Ritzer EE, Pandey A, Aggarwal D, Barwal TS, Jain A, Kaur G, Sak K, Varol M, Bishayee A. Molecular mechanisms of action of epigallocatechin gallate in cancer: Recent trends and advancement. Semin Cancer Biol 2022; 80:256-275. [PMID: 32461153 DOI: 10.1016/j.semcancer.2020.05.011] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/08/2020] [Accepted: 05/17/2020] [Indexed: 12/22/2022]
Abstract
Epigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is an ester of epigallocatechin and gallic acid. EGCG, abundantly found in tea, is a polyphenolic flavonoid that has the potential to affect human health and disease. EGCG interacts with various recognized cellular targets and inhibits cancer cell proliferation by inducing apoptosis and cell cycle arrest. In addition, scientific evidence has illustrated the promising role of EGCG in inhibiting tumor cell metastasis and angiogenesis. It has also been found that EGCG may reverse drug resistance of cancer cells and could be a promising candidate for synergism studies. The prospective importance of EGCG in cancer treatment is owed to its natural origin, safety, and low cost which presents it as an attractive target for further development of novel cancer therapeutics. A major challenge with EGCG is its low bioavailability which is being targeted for improvement by encapsulating EGCG in nano-sized vehicles for further delivery. However, there are major limitations of the studies on EGCG, including study design, experimental bias, and inconsistent results and reproducibility among different study cohorts. Additionally, it is important to identify specific EGCG pharmacological targets in the tumor-specific signaling pathways for development of novel combined therapeutic treatments with EGCG. The present review highlights the ongoing development to identify cellular and molecular targets of EGCG in cancer. Furthermore, the role of nanotechnology-mediated EGCG combinations and delivery systems will also be discussed.
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Affiliation(s)
- Vaishali Aggarwal
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, Punjab, India
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133 207, Haryana, India.
| | - Mousumi Tania
- Division of Molecular Cancer, Red Green Research Center, Dhaka 1205, Bangladesh
| | - Saumya Srivastava
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211 004, Uttar Pradesh, India
| | - Erin E Ritzer
- Lake Erie College of Osteopathic Medicine, Bradenton 34211, FL, USA
| | - Anjana Pandey
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211 004, Uttar Pradesh, India
| | - Diwakar Aggarwal
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133 207, Haryana, India
| | - Tushar Singh Barwal
- Department of Zoology, Central University of Punjab, Bathinda 151 001, Punjab, India
| | - Aklank Jain
- Department of Zoology, Central University of Punjab, Bathinda 151 001, Punjab, India
| | - Ginpreet Kaur
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, Mumbai 400 056, Maharastra, India
| | | | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Mugla Sitki Kocman University, Muğla TR48000, Turkey
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton 34211, FL, USA.
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Ashrafizadeh M, Zarrabi A, Mostafavi E, Aref AR, Sethi G, Wang L, Tergaonkar V. Non-coding RNA-based regulation of inflammation. Semin Immunol 2022; 59:101606. [PMID: 35691882 DOI: 10.1016/j.smim.2022.101606] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 05/01/2022] [Accepted: 05/25/2022] [Indexed: 01/15/2023]
Abstract
Inflammation is a multifactorial process and various biological mechanisms and pathways participate in its development. The presence of inflammation is involved in pathogenesis of different diseases such as diabetes mellitus, cardiovascular diseases and even, cancer. Non-coding RNAs (ncRNAs) comprise large part of transcribed genome and their critical function in physiological and pathological conditions has been confirmed. The present review focuses on miRNAs, lncRNAs and circRNAs as ncRNAs and their potential functions in inflammation regulation and resolution. Pro-inflammatory and anti-inflammatory factors are regulated by miRNAs via binding to 3'-UTR or indirectly via affecting other pathways such as SIRT1 and NF-κB. LncRNAs display a similar function and they can also affect miRNAs via sponging in regulating levels of cytokines. CircRNAs mainly affect miRNAs and reduce their expression in regulating cytokine levels. Notably, exosomal ncRNAs have shown capacity in inflammation resolution. In addition to pre-clinical studies, clinical trials have examined role of ncRNAs in inflammation-mediated disease pathogenesis and cytokine regulation. The therapeutic targeting of ncRNAs using drugs and nucleic acids have been analyzed to reduce inflammation in disease therapy. Therefore, ncRNAs can serve as diagnostic, prognostic and therapeutic targets in inflammation-related diseases in pre-clinical and clinical backgrounds.
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Affiliation(s)
- Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul, Turkey
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, 34396 Istanbul, Turkey.
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Translational Sciences, Xsphera Biosciences Inc. 6, Tide Street, Boston, MA 02210, USA
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
| | - Lingzhi Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology (IMCB), Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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Tuli HS, Mistry H, Kaur G, Aggarwal D, Garg VK, Mittal S, Yerer MB, Sak K, Khan MA. Gallic Acid: A Dietary Polyphenol that Exhibits Anti-neoplastic Activities by Modulating Multiple Oncogenic Targets. Anticancer Agents Med Chem 2022; 22:499-514. [PMID: 34802408 DOI: 10.2174/1871520621666211119085834] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/08/2021] [Accepted: 06/18/2021] [Indexed: 11/22/2022]
Abstract
Phytochemicals are being used for thousands of years to prevent dreadful malignancy. Side effects of existing allopathic treatment have also initiated intense research in the field of bioactive phytochemicals. Gallic acid, a natural polyphenolic compound, exists freely as well as in polymeric forms. The anti-cancer properties of gallic acid are indomitable by a variety of cellular pathways such as induction of programmed cell death, cell cycle apprehension, reticence of vasculature and tumor migration, and inflammation. Furthermore, gallic acid is found to show synergism with other existing chemotherapeutic drugs. Therefore, the antineoplastic role of gallic acid suggests its promising therapeutic candidature in the near future. The present review describes all these aspects of gallic acid at a single platform. In addition nanotechnology-mediated approaches are also discussed to enhance bioavailability and therapeutic efficacy.
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Affiliation(s)
- Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, India
| | - Hiral Mistry
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai 400056, Maharashtra, India
| | - Ginpreet Kaur
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai 400056, Maharashtra, India
| | - Diwakar Aggarwal
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, India
| | - Vivek Kumar Garg
- Department of Medical Laboratory Technology, University Institute of Applied Health Sciences, Chandigarh University, Gharuan, Mohali 140413, Punjab, India
| | - Sonam Mittal
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Mükerrem Betül Yerer
- Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Erciyes University Drug Application and Research Center, Kayseri, Turkey
| | | | - Md Asaduzzaman Khan
- The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, China
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Shanmugam MK, Sethi G. Molecular mechanisms of cell death. MECHANISMS OF CELL DEATH AND OPPORTUNITIES FOR THERAPEUTIC DEVELOPMENT 2022:65-92. [DOI: 10.1016/b978-0-12-814208-0.00002-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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Epithelial Mesenchymal Transition and its transcription factors. Biosci Rep 2021; 42:230017. [PMID: 34708244 PMCID: PMC8703024 DOI: 10.1042/bsr20211754] [Citation(s) in RCA: 140] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 10/26/2021] [Accepted: 10/28/2021] [Indexed: 11/17/2022] Open
Abstract
Epithelial–mesenchymal transition or EMT is an extremely dynamic process involved in conversion of epithelial cells into mesenchymal cells, stimulated by an ensemble of signaling pathways, leading to change in cellular morphology, suppression of epithelial characters and acquisition of properties such as enhanced cell motility and invasiveness, reduced cell death by apoptosis, resistance to chemotherapeutic drugs etc. Significantly, EMT has been found to play a crucial role during embryonic development, tissue fibrosis and would healing, as well as during cancer metastasis. Over the years, work from various laboratories have identified a rather large number of transcription factors (TFs) including the master regulators of EMT, with the ability to regulate the EMT process directly. In this review, we put together these EMT TFs and discussed their role in the process. We have also tried to focus on their mechanism of action, their interdependency, and the large regulatory network they form. Subsequently, it has become clear that the composition and structure of the transcriptional regulatory network behind EMT probably varies based upon various physiological and pathological contexts, or even in a cell/tissue type-dependent manner.
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Akıncılar SC, Wu L, NG QF, Chua JYH, Unal B, Noda T, Chor WHJ, Ikawa M, Tergaonkar V. NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis. Gut 2021; 70:1857-1871. [PMID: 33239342 PMCID: PMC8458091 DOI: 10.1136/gutjnl-2020-322980] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/19/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE NFκB is the key modulator in inflammatory disorders. However, the key regulators that activate, fine-tune or shut off NFκB activity in inflammatory conditions are poorly understood. In this study, we aim to investigate the roles that NFκB-specific long non-coding RNAs (lncRNAs) play in regulating inflammatory networks. DESIGN Using the first genetic-screen to identify NFκB-specific lncRNAs, we performed RNA-seq from the p65-/- and Ikkβ-/- mouse embryonic fibroblasts and report the identification of an evolutionary conserved lncRNA designated mNAIL (mice) or hNAIL (human). hNAIL is upregulated in human inflammatory disorders, including UC. We generated mNAILΔNFκB mice, wherein deletion of two NFκB sites in the proximal promoter of mNAIL abolishes its induction, to study its function in colitis. RESULTS NAIL regulates inflammation via sequestering and inactivating Wip1, a known negative regulator of proinflammatory p38 kinase and NFκB subunit p65. Wip1 inactivation leads to coordinated activation of p38 and covalent modifications of NFκB, essential for its genome-wide occupancy on specific targets. NAIL enables an orchestrated response for p38 and NFκB coactivation that leads to differentiation of precursor cells into immature myeloid cells in bone marrow, recruitment of macrophages to inflamed area and expression of inflammatory genes in colitis. CONCLUSION NAIL directly regulates initiation and progression of colitis and its expression is highly correlated with NFκB activity which makes it a perfect candidate to serve as a biomarker and a therapeutic target for IBD and other inflammation-associated diseases.
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Affiliation(s)
- Semih Can Akıncılar
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Institute of Molecular and Cell Biology, Singapore
| | - Lele Wu
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Institute of Molecular and Cell Biology, Singapore
| | - Qin Feng NG
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Institute of Molecular and Cell Biology, Singapore
| | - Joelle Yi Heng Chua
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Institute of Molecular and Cell Biology, Singapore
| | - Bilal Unal
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Institute of Molecular and Cell Biology, Singapore
| | - Taichi Noda
- Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Wei Hong Jeff Chor
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Institute of Molecular and Cell Biology, Singapore
| | - Masahito Ikawa
- Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Vinay Tergaonkar
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Institute of Molecular and Cell Biology, Singapore .,Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
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Bourova-Flin E, Derakhshan S, Goudarzi A, Wang T, Vitte AL, Chuffart F, Khochbin S, Rousseaux S, Aminishakib P. The combined detection of Amphiregulin, Cyclin A1 and DDX20/Gemin3 expression predicts aggressive forms of oral squamous cell carcinoma. Br J Cancer 2021; 125:1122-1134. [PMID: 34290392 PMCID: PMC8505643 DOI: 10.1038/s41416-021-01491-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/02/2021] [Accepted: 07/07/2021] [Indexed: 12/18/2022] Open
Abstract
Background Large-scale genetic and epigenetic deregulations enable cancer cells to ectopically activate tissue-specific expression programmes. A specifically designed strategy was applied to oral squamous cell carcinomas (OSCC) in order to detect ectopic gene activations and develop a prognostic stratification test. Methods A dedicated original prognosis biomarker discovery approach was implemented using genome-wide transcriptomic data of OSCC, including training and validation cohorts. Abnormal expressions of silent genes were systematically detected, correlated with survival probabilities and evaluated as predictive biomarkers. The resulting stratification test was confirmed in an independent cohort using immunohistochemistry. Results A specific gene expression signature, including a combination of three genes, AREG, CCNA1 and DDX20, was found associated with high-risk OSCC in univariate and multivariate analyses. It was translated into an immunohistochemistry-based test, which successfully stratified patients of our own independent cohort. Discussion The exploration of the whole gene expression profile characterising aggressive OSCC tumours highlights their enhanced proliferative and poorly differentiated intrinsic nature. Experimental targeting of CCNA1 in OSCC cells is associated with a shift of transcriptomic signature towards the less aggressive form of OSCC, suggesting that CCNA1 could be a good target for therapeutic approaches.
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Affiliation(s)
- Ekaterina Bourova-Flin
- CNRS UMR 5309/INSERM U1209/University Grenoble-Alpes/Institute for Advanced Biosciences, La Tronche, France
| | - Samira Derakhshan
- Oral and Maxillofacial Pathology Department, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Afsaneh Goudarzi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tao Wang
- CNRS UMR 5309/INSERM U1209/University Grenoble-Alpes/Institute for Advanced Biosciences, La Tronche, France
| | - Anne-Laure Vitte
- CNRS UMR 5309/INSERM U1209/University Grenoble-Alpes/Institute for Advanced Biosciences, La Tronche, France
| | - Florent Chuffart
- CNRS UMR 5309/INSERM U1209/University Grenoble-Alpes/Institute for Advanced Biosciences, La Tronche, France
| | - Saadi Khochbin
- CNRS UMR 5309/INSERM U1209/University Grenoble-Alpes/Institute for Advanced Biosciences, La Tronche, France
| | - Sophie Rousseaux
- CNRS UMR 5309/INSERM U1209/University Grenoble-Alpes/Institute for Advanced Biosciences, La Tronche, France.
| | - Pouyan Aminishakib
- Oral and Maxillofacial Pathology Department, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran. .,Cancer Institute Hospital, IKHC, Tehran University of Medical Sciences, Tehran, Iran.
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Ashrafizadeh M, Mirzaei S, Hashemi F, Zarrabi A, Zabolian A, Saleki H, Sharifzadeh SO, Soleymani L, Daneshi S, Hushmandi K, Khan H, Kumar AP, Aref AR, Samarghandian S. New insight towards development of paclitaxel and docetaxel resistance in cancer cells: EMT as a novel molecular mechanism and therapeutic possibilities. Biomed Pharmacother 2021; 141:111824. [PMID: 34175815 DOI: 10.1016/j.biopha.2021.111824] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/08/2021] [Accepted: 06/11/2021] [Indexed: 12/13/2022] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) mechanism is responsible for metastasis and migration of cancer cells to neighboring cells and tissues. Morphologically, epithelial cells are transformed to mesenchymal cells, and at molecular level, E-cadherin undergoes down-regulation, while an increase occurs in N-cadherin and vimentin levels. Increasing evidence demonstrates role of EMT in mediating drug resistance of cancer cells. On the other hand, paclitaxel (PTX) and docetaxel (DTX) are two chemotherapeutic agents belonging to taxene family, capable of inducing cell cycle arrest in cancer cells via preventing microtubule depolymerization. Aggressive behavior of cancer cells resulted from EMT-mediated metastasis can lead to PTX and DTX resistance. Upstream mediators of EMT such as ZEB1/2, TGF-β, microRNAs, and so on are involved in regulating response of cancer cells to PTX and DTX. Tumor-suppressing factors inhibit EMT to promote PTX and DTX sensitivity of cancer cells. Furthermore, three different strategies including using anti-tumor compounds, gene therapy and delivery systems have been developed for suppressing EMT, and enhancing cytotoxicity of PTX and DTX against cancer cells that are mechanistically discussed in the current review.
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Affiliation(s)
- Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956 Istanbul, Turkey
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Farid Hashemi
- Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956 Istanbul, Turkey
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Seyed Omid Sharifzadeh
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Leyla Soleymani
- Department of Biology, Faculty of Science, Urmia University, Urmia, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Vice President at Translational Sciences, Xsphera Biosciences Inc. 6 Tide Street, Boston, MA 02210, USA
| | - Saeed Samarghandian
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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Li Y, Shen QS, Peng Q, Ding W, Zhang J, Zhong X, An NA, Ji M, Zhou WZ, Li CY. Polyadenylation-related isoform switching in human evolution revealed by full-length transcript structure. Brief Bioinform 2021; 22:6273384. [PMID: 33973996 PMCID: PMC8574621 DOI: 10.1093/bib/bbab157] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/22/2021] [Accepted: 04/04/2021] [Indexed: 11/26/2022] Open
Abstract
Rhesus macaque is a unique nonhuman primate model for human evolutionary and translational study, but the error-prone gene models critically limit its applications. Here, we de novo defined full-length macaque gene models based on single molecule, long-read transcriptome sequencing in four macaque tissues (frontal cortex, cerebellum, heart and testis). Overall, 8 588 227 poly(A)-bearing complementary DNA reads with a mean length of 14 106 nt were generated to compile the backbone of macaque transcripts, with the fine-scale structures further refined by RNA sequencing and cap analysis gene expression sequencing data. In total, 51 605 macaque gene models were accurately defined, covering 89.7% of macaque or 75.7% of human orthologous genes. Based on the full-length gene models, we performed a human–macaque comparative analysis on polyadenylation (PA) regulation. Using macaque and mouse as outgroup species, we identified 79 distal PA events newly originated in humans and found that the strengthening of the distal PA sites, rather than the weakening of the proximal sites, predominantly contributes to the origination of these human-specific isoforms. Notably, these isoforms are selectively constrained in general and contribute to the temporospatially specific reduction of gene expression, through the tinkering of previously existed mechanisms of nuclear retention and microRNA (miRNA) regulation. Overall, the protocol and resource highlight the application of bioinformatics in integrating multilayer genomics data to provide an intact reference for model animal studies, and the isoform switching detected may constitute a hitherto underestimated regulatory layer in shaping the human-specific transcriptome and phenotypic changes.
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Affiliation(s)
- Yumei Li
- Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, Peking University, Beijing, China
| | - Qing Sunny Shen
- Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, Peking University, Beijing, China
| | - Qi Peng
- Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, Peking University, Beijing, China.,College of Future Technology, Peking University, Beijing, China
| | - Wanqiu Ding
- Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, Peking University, Beijing, China.,College of Future Technology, Peking University, Beijing, China
| | - Jie Zhang
- Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, Peking University, Beijing, China.,College of Future Technology, Peking University, Beijing, China
| | - Xiaoming Zhong
- Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, Peking University, Beijing, China
| | - Ni A An
- Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, Peking University, Beijing, China.,College of Future Technology, Peking University, Beijing, China
| | - Mingjun Ji
- Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, Peking University, Beijing, China.,College of Future Technology, Peking University, Beijing, China
| | - Wei-Zhen Zhou
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Beijing, China
| | - Chuan-Yun Li
- Laboratory of Bioinformatics and Genomic Medicine, Institute of Molecular Medicine, Peking University, Beijing, China.,College of Future Technology, Peking University, Beijing, China
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Datta A, Deng S, Gopal V, Yap KCH, Halim CE, Lye ML, Ong MS, Tan TZ, Sethi G, Hooi SC, Kumar AP, Yap CT. Cytoskeletal Dynamics in Epithelial-Mesenchymal Transition: Insights into Therapeutic Targets for Cancer Metastasis. Cancers (Basel) 2021; 13:1882. [PMID: 33919917 PMCID: PMC8070945 DOI: 10.3390/cancers13081882] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/08/2021] [Accepted: 04/12/2021] [Indexed: 12/14/2022] Open
Abstract
In cancer cells, a vital cellular process during metastasis is the transformation of epithelial cells towards motile mesenchymal cells called the epithelial to mesenchymal transition (EMT). The cytoskeleton is an active network of three intracellular filaments: actin cytoskeleton, microtubules, and intermediate filaments. These filaments play a central role in the structural design and cell behavior and are necessary for EMT. During EMT, epithelial cells undergo a cellular transformation as manifested by cell elongation, migration, and invasion, coordinated by actin cytoskeleton reorganization. The actin cytoskeleton is an extremely dynamic structure, controlled by a balance of assembly and disassembly of actin filaments. Actin-binding proteins regulate the process of actin polymerization and depolymerization. Microtubule reorganization also plays an important role in cell migration and polarization. Intermediate filaments are rearranged, switching to a vimentin-rich network, and this protein is used as a marker for a mesenchymal cell. Hence, targeting EMT by regulating the activities of their key components may be a potential solution to metastasis. This review summarizes the research done on the physiological functions of the cytoskeleton, its role in the EMT process, and its effect on multidrug-resistant (MDR) cancer cells-highlight some future perspectives in cancer therapy by targeting cytoskeleton.
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Affiliation(s)
- Arpita Datta
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (A.D.); (S.D.); (V.G.); (K.C.-H.Y.); (C.E.H.); (M.L.L.); (M.S.O.); (S.C.H.)
| | - Shuo Deng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (A.D.); (S.D.); (V.G.); (K.C.-H.Y.); (C.E.H.); (M.L.L.); (M.S.O.); (S.C.H.)
| | - Vennila Gopal
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (A.D.); (S.D.); (V.G.); (K.C.-H.Y.); (C.E.H.); (M.L.L.); (M.S.O.); (S.C.H.)
| | - Kenneth Chun-Hong Yap
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (A.D.); (S.D.); (V.G.); (K.C.-H.Y.); (C.E.H.); (M.L.L.); (M.S.O.); (S.C.H.)
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore;
| | - Clarissa Esmeralda Halim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (A.D.); (S.D.); (V.G.); (K.C.-H.Y.); (C.E.H.); (M.L.L.); (M.S.O.); (S.C.H.)
| | - Mun Leng Lye
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (A.D.); (S.D.); (V.G.); (K.C.-H.Y.); (C.E.H.); (M.L.L.); (M.S.O.); (S.C.H.)
| | - Mei Shan Ong
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (A.D.); (S.D.); (V.G.); (K.C.-H.Y.); (C.E.H.); (M.L.L.); (M.S.O.); (S.C.H.)
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117593, Singapore;
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore;
- Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
| | - Shing Chuan Hooi
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (A.D.); (S.D.); (V.G.); (K.C.-H.Y.); (C.E.H.); (M.L.L.); (M.S.O.); (S.C.H.)
- Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117593, Singapore;
- Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
- National University Cancer Institute, National University Health System, Singapore 119074, Singapore
| | - Celestial T. Yap
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; (A.D.); (S.D.); (V.G.); (K.C.-H.Y.); (C.E.H.); (M.L.L.); (M.S.O.); (S.C.H.)
- Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
- National University Cancer Institute, National University Health System, Singapore 119074, Singapore
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The DEAD-box protein family of RNA helicases: sentinels for a myriad of cellular functions with emerging roles in tumorigenesis. Int J Clin Oncol 2021; 26:795-825. [PMID: 33656655 DOI: 10.1007/s10147-021-01892-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/20/2021] [Indexed: 02/06/2023]
Abstract
DEAD-box RNA helicases comprise a family within helicase superfamily 2 and make up the largest group of RNA helicases. They are a profoundly conserved family of RNA-binding proteins, carrying a generic Asp-Glu-Ala-Asp (D-E-A-D) motif that gives the family its name. Members of the DEAD-box family of RNA helicases are engaged in all facets of RNA metabolism from biogenesis to decay. DEAD-box proteins ordinarily function as constituents of enormous multi-protein complexes and it is believed that interactions with other components in the complexes might be answerable for the various capacities ascribed to these proteins. Therefore, their exact function is probably impacted by their interacting partners and to be profoundly context dependent. This may give a clarification to the occasionally inconsistent reports proposing that DEAD-box proteins have both pro- and anti-proliferative functions in cancer. There is emerging evidence that DEAD-box family of RNA helicases play pivotal functions in various cellular processes and in numerous cases have been embroiled in cellular proliferation and/or neoplastic transformation. In various malignancy types, DEAD-box RNA helicases have been reported to possess pro-proliferation or even oncogenic roles as well as anti-proliferative or tumor suppressor functions. Clarifying the exact function of DEAD-box helicases in cancer is probably intricate, and relies upon the cellular milieu and interacting factors. This review aims to summarize the current data on the numerous capacities that have been ascribed to DEAD-box RNA helicases. It also highlights their diverse actions upon malignant transformation in the various tumor types.
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Shin EM, Huynh VT, Neja SA, Liu CY, Raju A, Tan K, Tan NS, Gunaratne J, Bi X, Iyer LM, Aravind L, Tergaonkar V. GREB1: An evolutionarily conserved protein with a glycosyltransferase domain links ERα glycosylation and stability to cancer. SCIENCE ADVANCES 2021; 7:7/12/eabe2470. [PMID: 33731348 PMCID: PMC7968844 DOI: 10.1126/sciadv.abe2470] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 01/29/2021] [Indexed: 05/03/2023]
Abstract
What covalent modifications control the temporal ubiquitination of ERα and hence the duration of its transcriptional activity remain poorly understood. We show that GREB1, an ERα-inducible enzyme, catalyzes O-GlcNAcylation of ERα at residues T553/S554, which stabilizes ERα protein by inhibiting association with the ubiquitin ligase ZNF598. Loss of GREB1-mediated glycosylation of ERα results in reduced cellular ERα levels and insensitivity to estrogen. Higher GREB1 expression in ERα+ve breast cancer is associated with greater survival in response to tamoxifen, an ERα agonist. Mice lacking Greb1 exhibit growth and fertility defects reminiscent of phenotypes in ERα-null mice. In summary, this study identifies GREB1, a protein with an evolutionarily conserved domain related to DNA-modifying glycosyltransferases of bacteriophages and kinetoplastids, as the first inducible and the only other (apart from OGT) O-GlcNAc glycosyltransferase in mammalian cytoplasm and ERα as its first substrate.
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Affiliation(s)
- Eun Myoung Shin
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research, Singapore 138673, Singapore
| | - Vinh Thang Huynh
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research, Singapore 138673, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Sultan Abda Neja
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research, Singapore 138673, Singapore
| | - Chia Yi Liu
- Bioprocessing Technology Institute (BTI), A*STAR, Singapore, Singapore
| | - Anandhkumar Raju
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research, Singapore 138673, Singapore
| | - Kelly Tan
- Bioprocessing Technology Institute (BTI), A*STAR, Singapore, Singapore
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive,, Singapore 637551, Singapore
| | - Jayantha Gunaratne
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research, Singapore 138673, Singapore
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 117594, Singapore
| | - Xuezhi Bi
- Bioprocessing Technology Institute (BTI), A*STAR, Singapore, Singapore
- Duke-NUS Medical School, Singapore 169857, Singapore
| | - Lakshminarayan M Iyer
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA
| | - L Aravind
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA
| | - Vinay Tergaonkar
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research, Singapore 138673, Singapore.
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 117597, Singapore
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Small in Size, but Large in Action: microRNAs as Potential Modulators of PTEN in Breast and Lung Cancers. Biomolecules 2021; 11:biom11020304. [PMID: 33670518 PMCID: PMC7922700 DOI: 10.3390/biom11020304] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/15/2021] [Accepted: 02/15/2021] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs) are well-known regulators of biological mechanisms with a small size of 19–24 nucleotides and a single-stranded structure. miRNA dysregulation occurs in cancer progression. miRNAs can function as tumor-suppressing or tumor-promoting factors in cancer via regulating molecular pathways. Breast and lung cancers are two malignant thoracic tumors in which the abnormal expression of miRNAs plays a significant role in their development. Phosphatase and tensin homolog (PTEN) is a tumor-suppressor factor that is capable of suppressing the growth, viability, and metastasis of cancer cells via downregulating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling. PTEN downregulation occurs in lung and breast cancers to promote PI3K/Akt expression, leading to uncontrolled proliferation, metastasis, and their resistance to chemotherapy and radiotherapy. miRNAs as upstream mediators of PTEN can dually induce/inhibit PTEN signaling in affecting the malignant behavior of lung and breast cancer cells. Furthermore, long non-coding RNAs and circular RNAs can regulate the miRNA/PTEN axis in lung and breast cancer cells. It seems that anti-tumor compounds such as baicalein, propofol, and curcumin can induce PTEN upregulation by affecting miRNAs in suppressing breast and lung cancer progression. These topics are discussed in the current review with a focus on molecular pathways.
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36
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Tan EE, Hopkins RA, Lim CK, Jamuar SS, Ong C, Thoon KC, Koh MJ, Shin EM, Lian DW, Weerasooriya M, Lee CZ, Soetedjo AAP, Lim CS, Au VB, Chua E, Lee HY, Jones LA, James SS, Kaliaperumal N, Kwok J, Tan ES, Thomas B, Wu LX, Ho L, Fairhurst AM, Ginhoux F, Teo AK, Zhang YL, Ong KH, Yu W, Venkatesh B, Tergaonkar V, Reversade B, Chin KC, Tan AM, Liew WK, Connolly JE. Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency. J Clin Invest 2021; 130:5817-5832. [PMID: 32750042 DOI: 10.1172/jci98882] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 07/16/2020] [Indexed: 12/12/2022] Open
Abstract
Although IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1β expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1β secretion was elevated in the patient's stimulated leukocytes, in her induced pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient's hypersecretion of IL-1β correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1β release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1β secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.
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Affiliation(s)
- Enrica Ek Tan
- Department of Paediatric Subspecialties, KK Women's and Children's Hospital, Singapore.,Duke-NUS Medical School, Singapore
| | - Richard A Hopkins
- Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Chrissie K Lim
- Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Saumya S Jamuar
- Department of Paediatric Subspecialties, KK Women's and Children's Hospital, Singapore.,Duke-NUS Medical School, Singapore
| | - Christina Ong
- Duke-NUS Medical School, Singapore.,Department of Paediatrics and
| | - Koh C Thoon
- Duke-NUS Medical School, Singapore.,Department of Paediatrics and
| | - Mark Ja Koh
- Duke-NUS Medical School, Singapore.,Dermatology Service, KK Women's and Children's Hospital, Singapore
| | - Eun Mong Shin
- Institute of Molecular and Cell Biology, A*STAR, Singapore.,Cancer Science Institute of Singapore, Singapore.,National University of Singapore, Singapore
| | - Derrick Wq Lian
- Department of Paediatric Subspecialties, KK Women's and Children's Hospital, Singapore.,Duke-NUS Medical School, Singapore.,Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Madhushanee Weerasooriya
- Department of Microbiology and Immunology and.,Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore
| | | | | | | | - Veonice B Au
- Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Edmond Chua
- Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Hui Yin Lee
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Leigh Ann Jones
- Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Sharmy S James
- Department of Microbiology and Immunology and.,Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore
| | - Nivashini Kaliaperumal
- Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Jeffery Kwok
- Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Ee Shien Tan
- Duke-NUS Medical School, Singapore.,Department of Paediatrics and
| | - Biju Thomas
- Duke-NUS Medical School, Singapore.,Department of Paediatrics and
| | - Lynn Xue Wu
- Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Lena Ho
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | | | | | - Adrian Kk Teo
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Yong Liang Zhang
- Department of Microbiology and Immunology and.,Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore
| | - Kok Huar Ong
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Weimiao Yu
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | | | - Vinay Tergaonkar
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology, A*STAR, Singapore.,Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.,Faculty of Health Sciences, University of Macau, Macau, China
| | - Bruno Reversade
- Institute of Molecular and Cell Biology, A*STAR, Singapore.,Department of Medical Genetics, School of Medicine, Koç University, Istanbul, Turkey.,Department of Paediatrics, National University of Singapore, Singapore.,Institute of Medical Biology, A*STAR, Singapore
| | - Keh Chuang Chin
- Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore.,Department of Physiology and
| | | | - Woei Kang Liew
- Duke-NUS Medical School, Singapore.,Department of Paediatrics and
| | - John E Connolly
- Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore.,Department of Paediatrics and.,Department of Microbiology and Immunity, National University of Singapore, Singapore.,Institute of Biomedical Studies, Baylor University Medical Center, Waco, Texas, USA
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37
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Shang W, Wang Y, Liang X, Li T, Shao W, Liu F, Cui X, Wang Y, Lv L, Chai L, Qu L, Zheng L, Jia J. SETDB1 promotes gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9 expression. J Pathol 2021; 253:148-159. [PMID: 33044755 DOI: 10.1002/path.5568] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 09/20/2020] [Accepted: 10/07/2020] [Indexed: 12/19/2022]
Abstract
SETDB1 is a histone lysine methyltransferase that has critical roles in cancers. However, its potential role in gastric cancer (GC) remains obscure. Here, we mainly investigate the clinical significance and the possible role of SETDB1 in GC. We find that SETDB1 expression is upregulated in GC tissues and its high-level expression was a predictor of poor prognosis in patients. Overexpression of SETDB1 promoted cell proliferation and metastasis, while SETDB1 suppression had an opposite effect both in vitro and in vivo. Mechanistically, SETDB1 was shown to interact with ERG to promote the transcription of cyclin D1 (CCND1) and matrix metalloproteinase 9 (MMP9) through binding to their promoter regions. In addition, the expression of SETDB1 was also enhanced by the transcription factor TCF4 at the transcriptional level in GC. Furthermore, SETDB1 expression was found to be induced by Helicobacter pylori (H. pylori) infection in a TCF4-dependent manner. Taken together, our results indicate that SETDB1 is aberrantly overexpressed in GC and plays key roles in gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9. Our work also suggests that SETDB1 could be a potential oncogenic factor and a therapeutic target for GC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Wenjing Shang
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
- Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Yue Wang
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Xiuming Liang
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
- Shandong University-Karolinska Institute Collaborative Laboratory for Cancer Research, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Tongyu Li
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Wei Shao
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Fen Liu
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Xiujie Cui
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Yuanyuan Wang
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Lin Lv
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Li Chai
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Lingxin Qu
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Lixin Zheng
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Jihui Jia
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
- Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
- Shandong University-Karolinska Institute Collaborative Laboratory for Cancer Research, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, PR China
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38
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Brucein D modulates MAPK signaling cascade to exert multi-faceted anti-neoplastic actions against breast cancer cells. Biochimie 2021; 182:140-151. [PMID: 33484785 DOI: 10.1016/j.biochi.2021.01.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/30/2020] [Accepted: 01/15/2021] [Indexed: 02/07/2023]
Abstract
Breast cancer is a prominent type of malignancy among women with a high rate of mortality. A number of previous studies have demonstrated the anticancer potential of brucein D (BD), a quassinoid extracted from Brucea javanica, against the cancers of the pancreas, bone, and liver. We investigated the impact of BD on apoptotic as well on mitogen-activated protein kinase (MAPK) signaling cascades in breast cancer cells. The effect of BD on p38 MAPK and JNK signaling pathways and its downstream functions was deciphered in both MDA-MB-231 and MCF-7 cell lines. We noted that BD decreased the viability of breast cancer cells without affecting the growth of healthy mammary epithelial cells (MCF-10A). Flow cytometric analysis revealed that BD can increase sub-G1 cells and enhanced annexin-V-PI stained cells. The apoptogenic impact of BD was further substantiated by cleavage of procaspase-3/8 and downregulation of antiapoptotic proteins (Bcl-xL, XIAP, and survivin). Furthermore, BD also downmodulated the migratory ability, and chemokine triggered invasion of breast cancer cells. Interestingly, the pharmacological inhibition of p38 MAPK and JNK kinases abrogated the observed anticancer actions of BD. Overall, the data indicated that BD can induce substantial apoptosis and interfere with cellular invasion by modulating MAPK signaling pathway in breast cancer cells.
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39
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Aggarwal V, Kumar G, Aggarwal D, Yerer MB, Cumaoğlu A, Kumar M, Sak K, Mittal S, Tuli HS, Sethi G. Cancer preventive role of olives and olive oil via modulation of apoptosis and nuclear factor-kappa B activation. OLIVES AND OLIVE OIL IN HEALTH AND DISEASE PREVENTION 2021:377-388. [DOI: 10.1016/b978-0-12-819528-4.00005-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2024]
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40
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Ronzio M, Bernardini A, Pavesi G, Mantovani R, Dolfini D. On the NF-Y regulome as in ENCODE (2019). PLoS Comput Biol 2020; 16:e1008488. [PMID: 33370256 PMCID: PMC7793273 DOI: 10.1371/journal.pcbi.1008488] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 01/08/2021] [Accepted: 11/04/2020] [Indexed: 11/19/2022] Open
Abstract
NF-Y is a trimeric Transcription Factor -TF- which binds with high selectivity to the conserved CCAAT element. Individual ChIP-seq analysis as well as ENCODE have progressively identified locations shared by other TFs. Here, we have analyzed data introduced by ENCODE over the last five years in K562, HeLa-S3 and GM12878, including several chromatin features, as well RNA-seq profiling of HeLa cells after NF-Y inactivation. We double the number of sequence-specific TFs and co-factors reported. We catalogue them in 4 classes based on co-association criteria, infer target genes categorizations, identify positional bias of binding sites and gene expression changes. Larger and novel co-associations emerge, specifically concerning subunits of repressive complexes as well as RNA-binding proteins. On the one hand, these data better define NF-Y association with single members of major classes of TFs, on the other, they suggest that it might have a wider role in the control of mRNA production. The ongoing ENCODE consortium represents a useful compendium of locations of TFs, chromatin marks, gene expression data. In previous reports, we identified modules of CCAAT-binding NF-Y with individual TFs. Here, we analyzed all 363 factors currently present: 68 with enrichment of CCAAT in their locations, 38 with overlap of peaks. New sequence-specific TFs, co-activators and co-repressors are reported. Co-association patterns correspond to specific targeted genes categorizations and gene expression changes, as assessed by RNA-seq after NF-Y inactivation. These data widen and better define a coherent model of synergy of NF-Y with selected groups of TFs and co-factors.
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Affiliation(s)
- Mirko Ronzio
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Andrea Bernardini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Giulio Pavesi
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Roberto Mantovani
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Diletta Dolfini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
- * E-mail:
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41
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Venom peptides in cancer therapy: An updated review on cellular and molecular aspects. Pharmacol Res 2020; 164:105327. [PMID: 33276098 DOI: 10.1016/j.phrs.2020.105327] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 11/25/2020] [Accepted: 11/27/2020] [Indexed: 02/07/2023]
Abstract
Based on the high incidence and mortality rates of cancer, its therapy remains one of the most vital challenges in the field of medicine. Consequently, enhancing the efficacy of currently applied treatments and finding novel strategies are of great importance for cancer treatment. Venoms are important sources of a variety of bioactive compounds including salts, small molecules, macromolecules, proteins, and peptides that are defined as toxins. They can exhibit different pharmacological effects, and in recent years, their anti-tumor activities have gained significant attention. Several different compounds are responsible for the anti-tumor activity of venoms, and peptides are one of them. In the present review, we discuss the possible anti-tumor activities of venom peptides by highlighting molecular pathways and mechanisms through which these molecules can act effectively. Venom peptides can induce cell death in cancer cells and can substantially enhance the efficacy of chemotherapy and radiotherapy. Also, the venom peptides can mitigate the migration of cancer cells via suppression of angiogenesis and epithelial-to-mesenchymal transition. Notably, nanoparticles have been applied in enhancing the bioavailability of venom peptides and providing targeted delivery, thereby leading to their elevated anti-tumor activity and potential application for cancer therapy.
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42
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Kirtonia A, Sethi G, Garg M. The multifaceted role of reactive oxygen species in tumorigenesis. Cell Mol Life Sci 2020; 77:4459-4483. [PMID: 32358622 PMCID: PMC11105050 DOI: 10.1007/s00018-020-03536-5] [Citation(s) in RCA: 280] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 03/29/2020] [Accepted: 04/20/2020] [Indexed: 02/06/2023]
Abstract
Redox homeostasis is an essential requirement of the biological systems for performing various normal cellular functions including cellular growth, differentiation, senescence, survival and aging in humans. The changes in the basal levels of reactive oxygen species (ROS) are detrimental to cells and often lead to several disease conditions including cardiovascular, neurological, diabetes and cancer. During the last two decades, substantial research has been done which clearly suggests that ROS are essential for the initiation, progression, angiogenesis as well as metastasis of cancer in several ways. During the last two decades, the potential of dysregulated ROS to enhance tumor formation through the activation of various oncogenic signaling pathways, DNA mutations, immune escape, tumor microenvironment, metastasis, angiogenesis and extension of telomere has been discovered. At present, surgery followed by chemotherapy and/or radiotherapy is the major therapeutic modality for treating patients with either early or advanced stages of cancer. However, the majority of patients relapse or did not respond to initial treatment. One of the reasons for recurrence/relapse is the altered levels of ROS in tumor cells as well as in cancer-initiating stem cells. One of the critical issues is targeting the intracellular/extracellular ROS for significant antitumor response and relapse-free survival. Indeed, a large number of FDA-approved anticancer drugs are efficient to eliminate cancer cells and drug resistance by increasing ROS production. Thus, the modulation of oxidative stress response might represent a potential approach to eradicate cancer in combination with FDA-approved chemotherapies, radiotherapies as well as immunotherapies.
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Affiliation(s)
- Anuradha Kirtonia
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Campus, Sector-125, Noida, Uttar Pradesh, 201313, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Campus, Sector-125, Noida, Uttar Pradesh, 201313, India.
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43
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Girisa S, Parama D, Harsha C, Banik K, Kunnumakkara AB. Potential of guggulsterone, a farnesoid X receptor antagonist, in the prevention and treatment of cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:313-342. [PMID: 36046484 PMCID: PMC9400725 DOI: 10.37349/etat.2020.00019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer is one of the most dreadful diseases in the world with a mortality of 9.6 million annually. Despite the advances in diagnosis and treatment during the last couple of decades, it still remains a serious concern due to the limitations associated with currently available cancer management strategies. Therefore, alternative strategies are highly required to overcome these glitches. The importance of medicinal plants as primary healthcare has been well-known from time immemorial against various human diseases, including cancer. Commiphora wightii that belongs to Burseraceae family is one such plant which has been used to cure various ailments in traditional systems of medicine. This plant has diverse pharmacological properties such as antioxidant, antibacterial, antimutagenic, and antitumor which mostly owes to the presence of its active compound guggulsterone (GS) that exists in the form of Z- and E-isomers. Mounting evidence suggests that this compound has promising anticancer activities and was shown to suppress several cancer signaling pathways such as NF-κB/ERK/MAPK/AKT/STAT and modulate the expression of numerous signaling molecules such as the farnesoid X receptor, cyclin D1, survivin, caspases, HIF-1α, MMP-9, EMT proteins, tumor suppressor proteins, angiogenic proteins, and apoptotic proteins. The current review is an attempt to summarize the biological activities and diverse anticancer activities (both in vitro and in vivo) of the compound GS and its derivatives, along with its associated mechanism against various cancers.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
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44
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Tuli HS, Aggarwal V, Kaur J, Aggarwal D, Parashar G, Parashar NC, Tuorkey M, Kaur G, Savla R, Sak K, Kumar M. Baicalein: A metabolite with promising antineoplastic activity. Life Sci 2020; 259:118183. [PMID: 32781058 DOI: 10.1016/j.lfs.2020.118183] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/22/2020] [Accepted: 07/28/2020] [Indexed: 12/11/2022]
Abstract
Cancer, being a multifactorial disease has diverse presentation in different subgroups which is mainly attributed to heterogenous presentation of tumor cells. This cancer cell heterogeneity is the major reason for variable response to standard chemotherapeutic regimes owing to which high relapse rate and multi-drug resistance has increasingly been reported over the past decade. Interestingly, the research on natural compounds in combination with standard therapies have reported with interesting and promising results from the pre-clinical trials and few of which have also been tested in other phases of clinical trials. This review focusses on baicalein, an emerging anti-cancerous natural compound, its chemistry and mechanism of action. In view of promising pre-clinical this review is mainly motivated by the results observed from baicalein treatment of different cancer cell population. With the advancing scientific evidence on the anti-malignant potential of baicalein with respect to its pharmacological activities encompassing from anti-inflammatory to anti-angiogenic/anti-metastatic effects, the focus is mainly directed to understanding the precise mechanism of action of baicalein. In the process of understanding the underlying signaling cascades, the role of mitogen activated protein kinase (MAPK), mammalian target of rapamycin (mTOR), AKT serine/threonine protein kinase B (AKT), poly(ADP-ribose) polymerase (PARP), matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9) and caspase-3/-8,-9 have been highlighted as the major players for baicalein anti-malignant potential. This is also supported by the interesting pre-clinical findings which cumulatively pave the way ahead for development of baicalein as an adjunct anti-cancer treatment with chemotherapeutic agents.
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Affiliation(s)
- Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana 133207, India.
| | - Vaishali Aggarwal
- Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, Punjab 160012, India
| | - Jagjit Kaur
- Graduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics (CNBP), Faculty of Engineering, The University of New South Wales, Sydney 2052, Australia
| | - Diwakar Aggarwal
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana 133207, India
| | - Gaurav Parashar
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana 133207, India
| | | | - Muobarak Tuorkey
- Division of Physiology, Zoology Department, Faculty of Science, Damanhour University, Damanhour, Egypt
| | - Ginpreet Kaur
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, Vileparle-West, Mumbai-56, India
| | - Raj Savla
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, Vileparle-West, Mumbai-56, India
| | | | - Manoj Kumar
- Department of Chemistry, Maharishi Markandeshwar University, Sadopur, India
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45
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Wang Q, Ye Y, Lin R, Weng S, Cai F, Zou M, Niu H, Ge L, Lin Y. Analysis of the expression, function, prognosis and co-expression genes of DDX20 in gastric cancer. Comput Struct Biotechnol J 2020; 18:2453-2462. [PMID: 33005307 PMCID: PMC7509587 DOI: 10.1016/j.csbj.2020.09.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/29/2020] [Accepted: 09/01/2020] [Indexed: 01/04/2023] Open
Abstract
DDX20 (DEAD-box polypeptide 20) is implicated in many cellular processes involving alteration of RNA secondary structure. The role of DDX20 in gastric cancer is still unknown. In the research, the expression of DDX20 and the functional roles of DDX20 in gastric cancer were detected. The increased DDX20 expression in gastric cancer tissue compared with normal gastric tissue was observed. Functional experiments indicated that DDX20 promoted gastric cancer MGC-803 and AGS cells growth, migration, and invasion in vitro. Surprisingly, survival analysis showed that high expression of DDX20 is a favorable prognostic factor for patients with gastric cancer. In addition, enrichment analysis revealed that there is a positive correlation between DDX20 expression and T cell activation in gastric cancer. but not in normal gastric tissues. Furthermore, we found that DDX20 expression level has significant positive correlations with activated CD8 + T cells and activated CD4 + T cells in gastric cancer. Therefore, we hypothesize that the prognostic role of DDX20 in gastric cancer patients may be due to patients with high DDX20 expression contained better immune activation. Taken together, these findings suggest that DDX20 can promote the progression of gastric cancer in vitro and its prognostic value in gastric cancer may be related to many factors, including immune activation.
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Affiliation(s)
- Qingshui Wang
- Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province 210000, China.,Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province 350117, China.,The Engineering Technology Research Center of Characteristic Medicinal Plants of Fujian, Ningde Normal University, Ningde, Fujian Province 352100, China.,Fujian Provincial Key Laboratory of Hepatic Drug Research, Fuzhou, Fujian Province 350014, China
| | - Yan Ye
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province 350117, China
| | - Rongbo Lin
- Department of Gastrointestinal Medical Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian Province 350014, China
| | - Shuyun Weng
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province 350117, China
| | - Fan Cai
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province 350117, China
| | - Mei Zou
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province 350117, China
| | - Haitao Niu
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province 350117, China
| | - Lilin Ge
- Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province 210000, China
| | - Yao Lin
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province 350117, China.,Central Laboratory at The Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Collaborative Innovation Center for Rehabilitation Technology, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province 350014, China
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46
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Andrijauskaite K, Wargovich MJ. Role of natural products in breast cancer related symptomology: Targeting chronic inflammation. Semin Cancer Biol 2020; 80:370-378. [PMID: 32891720 DOI: 10.1016/j.semcancer.2020.08.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 08/03/2020] [Accepted: 08/16/2020] [Indexed: 02/06/2023]
Abstract
Breast cancer is the most common cancer in women worldwide. There have been many advancements in the treatment of breast cancer leading to an increased population of patients living with this disease. Accumulating evidence suggests that cancer diagnosis and aftermath experienced stress could not only affect the quality of life of cancer patients, but it could also influence their disease outcome. The magnitude of stress experienced by breast cancer patients is often compared to the post-traumatic stress disorder-like symptoms suggested to be mediated by the chronic inflammation including NF-κB, AKt, p53 and other inflammatory pathways. Here, we describe the symptomology of PTSD-like symptoms in breast cancer patients and argue that they may in fact be caused by or maintained through aspects of chronic inflammation mediated by the pro-inflammatory markers. Evidence exists that natural products that might attenuate or lessen the effects of chronic inflammation abound in the diet. We summarize some possible agents that might abate the genesis of symptoms experienced by breast cancer patients while mitigating the effect of inflammation.
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Affiliation(s)
- Kristina Andrijauskaite
- Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, 78229, United States.
| | - Michael J Wargovich
- Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, 78229, United States
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47
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Shahzadi I, Ali Z, Bukhari S, Narula AS, Mirza B, Mohammadinejad R. Possible applications of salvianolic acid B against different cancers. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:218-238. [PMID: 36046777 PMCID: PMC9400738 DOI: 10.37349/etat.2020.00014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/06/2020] [Indexed: 12/14/2022] Open
Abstract
Cancer is the second death causing disease worldwide after cardiovascular abnormalities. The difficulty in treating tumor cells with more precise targeted interventions and recurrence of cancer after treatment may pose great difficulty in developing sustainable therapeutic regimens. These limitations have prompted the need to explore several compounds with ability to cease tumor growth while at the same time induce apoptosis of tumor cells. Several studies have emphasized the use of natural compounds as antitumor agents due to their high efficacy against cancer cells and low toxicity in normal cells. Salvianolic acid B (SAB), a naturally occurring phenolic compound extracted from the radix of Chinese herb Salvia miltiorrhiza can induce apoptosis in different types of tumor cells. It can be used to treat cardiovascular and neurodegenerative disorders, hepatic fibrosis, and cancers. Several studies have shown that SAB can mitigate tumorigenesis by modulating MAPK, PI3K/AKT, and NF-ĸB signaling pathways. It also sensitizes the tumor cells to different anti-cancer agents by reversing the multi-drug resistance mechanisms found in tumor cells. This review summarizes the studies showing antitumor potential of SAB in different types of cancer cell lines, animal models and highlights the possible mechanisms through which SAB can induce apoptosis, inhibit growth and metastasis in tumor cells. Moreover, the possible role of nano-technological approaches to induce targeted delivery of SAB to eradicate tumor cells has been also discussed.
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Affiliation(s)
- Iram Shahzadi
- Plant Molecular Biology Lab, Institute of Biological Sciences, Department of Biochemistry, Quaid i Azam University, Islamabad 45320, Pakistan
| | - Zain Ali
- Molecular Cancer Therapeutics Lab, Institute of Biological Sciences, Department of Biochemistry, Quaid i Azam University, Islamabad 45320, Pakistan
| | - Sidra Bukhari
- Molecular Cancer Therapeutics Lab, Institute of Biological Sciences, Department of Biochemistry, Quaid i Azam University, Islamabad 45320, Pakistan; Naula Research, Chapel Hill, NC 27516, USA
| | | | - Bushra Mirza
- Plant Molecular Biology Lab, Institute of Biological Sciences, Department of Biochemistry, Quaid i Azam University, Islamabad 45320, Pakistan
| | - Reza Mohammadinejad
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7619813159, Iran
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48
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Parama D, Boruah M, Yachna K, Rana V, Banik K, Harsha C, Thakur KK, Dutta U, Arya A, Mao X, Ahn KS, Kunnumakkara AB. Diosgenin, a steroidal saponin, and its analogs: Effective therapies against different chronic diseases. Life Sci 2020; 260:118182. [PMID: 32781063 DOI: 10.1016/j.lfs.2020.118182] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/24/2020] [Accepted: 07/28/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic diseases are a major cause of mortality worldwide, and despite the recent development in treatment modalities, synthetic drugs have continued to show toxic side effects and development of chemoresistance, thereby limiting their application. The use of phytochemicals has gained attention as they show minimal side effects. Diosgenin is one such phytochemical which has gained importance for its efficacy against the life-threatening diseases, such as cardiovascular diseases, cancer, nervous system disorders, asthma, arthritis, diabetes, and many more. AIM To evaluate the literature available on the potential of diosgenin and its analogs in modulating different molecular targets leading to the prevention and treatment of chronic diseases. METHOD A detailed literature search has been carried out on PubMed for gathering information related to the sources, biosynthesis, physicochemical properties, biological activities, pharmacokinetics, bioavailability and toxicity of diosgenin and its analogs. KEY FINDINGS The literature search resulted in many in vitro, in vivo and clinical trials that reported the efficacy of diosgenin and its analogs in modulating important molecular targets and signaling pathways such as PI3K/AKT/mTOR, JAK/STAT, NF-κB, MAPK, etc., which play a crucial role in the development of most of the diseases. Reports have also revealed the safety of the compound and the adaptation of nanotechnological approaches for enhancing its bioavailability and pharmacokinetic properties. SIGNIFICANCE Thus, the review summarizes the efficacy of diosgenin and its analogs for developing as a potent drug against several chronic diseases.
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Affiliation(s)
- Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Monikongkona Boruah
- Cell and Molecular Biology Lab, Department of Zoology, Cotton University, Guwahati, Assam 781001, India
| | - Kumari Yachna
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Krishan Kumar Thakur
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Uma Dutta
- Cell and Molecular Biology Lab, Department of Zoology, Cotton University, Guwahati, Assam 781001, India
| | - Aditya Arya
- Department of Pharmacology and Therapeutics, School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Xinliang Mao
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, 12 Jichang Road, Baiyun District, Guangzhou 510405, China; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India.
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49
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Ashrafizadeh M, Najafi M, Ang HL, Moghadam ER, Mahabady MK, Zabolian A, Jafaripour L, Bejandi AK, Hushmandi K, Saleki H, Zarrabi A, Kumar AP. PTEN, a Barrier for Proliferation and Metastasis of Gastric Cancer Cells: From Molecular Pathways to Targeting and Regulation. Biomedicines 2020; 8:E264. [PMID: 32756305 PMCID: PMC7460532 DOI: 10.3390/biomedicines8080264] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/23/2020] [Accepted: 07/23/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer is one of the life-threatening disorders that, in spite of excellent advances in medicine and technology, there is no effective cure for. Surgery, chemotherapy, and radiotherapy are extensively applied in cancer therapy, but their efficacy in eradication of cancer cells, suppressing metastasis, and improving overall survival of patients is low. This is due to uncontrolled proliferation of cancer cells and their high migratory ability. Finding molecular pathways involved in malignant behavior of cancer cells can pave the road to effective cancer therapy. In the present review, we focus on phosphatase and tensin homolog (PTEN) signaling as a tumor-suppressor molecular pathway in gastric cancer (GC). PTEN inhibits the PI3K/Akt pathway from interfering with the migration and growth of GC cells. Its activation leads to better survival of patients with GC. Different upstream mediators of PTEN in GC have been identified that can regulate PTEN in suppressing growth and invasion of GC cells, such as microRNAs, long non-coding RNAs, and circular RNAs. It seems that antitumor agents enhance the expression of PTEN in overcoming GC. This review focuses on aforementioned topics to provide a new insight into involvement of PTEN and its downstream and upstream mediators in GC. This will direct further studies for evaluation of novel signaling networks and their targeting for suppressing GC progression.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz 5166616471, Iran;
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran;
| | - Hui Li Ang
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore;
| | - Ebrahim Rahmani Moghadam
- Department of Anatomical Sciences, School of Medicine, Student Research Committee, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran;
- Kazerun Health Technology Incubator, Shiraz University of Medical Sciences, Shiraz 6461665145, Iran
| | - Mahmood Khaksary Mahabady
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan 8715988141, Iran;
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1916893813, Iran; (A.Z.); (A.K.B.); (H.S.)
| | - Leila Jafaripour
- Department of Anatomy, School of Medicine, Dezful University of Medical Sciences, Dezful 3419759811, Iran;
| | - Atefe Kazemzade Bejandi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1916893813, Iran; (A.Z.); (A.K.B.); (H.S.)
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran 1417414418, Iran;
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1916893813, Iran; (A.Z.); (A.K.B.); (H.S.)
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey
- Center of Excellence for Functional Surfaces and Interfaces (EFSUN), Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla 34956, Istanbul, Turkey
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore;
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50
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Huang Y, Wang C, Li K, Ye Y, Shen A, Guo L, Chen P, Meng C, Wang Q, Yang X, Huang Z, Xing X, Lin Y, Liu X, Peng J, Lin Y. Death-associated protein kinase 1 suppresses hepatocellular carcinoma cell migration and invasion by upregulation of DEAD-box helicase 20. Cancer Sci 2020; 111:2803-2813. [PMID: 32449268 PMCID: PMC7419049 DOI: 10.1111/cas.14499] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/12/2020] [Accepted: 05/15/2020] [Indexed: 01/21/2023] Open
Abstract
Death-associated protein kinase 1 (DAPK) is a calcium/calmodulin kinase that plays a vital role as a suppressor gene in various cancers. Yet its role and target gene independent of p53 is still unknown in hepatocellular carcinoma (HCC). In this study, we discovered that DAPK suppressed HCC cell migration and invasion instead of proliferation or colony formation. Using a proteomics approach, we identified DEAD-box helicase 20 (DDX20) as an important downstream target of DAPK in HCC cells and critical for DAPK-mediated inhibition of HCC cell migration and invasion. Using integrin inhibitor RGD and GTPase activity assays, we discovered that DDX20 suppressed HCC cell migration and invasion through the CDC42-integrin pathway, which was previously reported as an important downstream pathway of DAPK in cancer. Further research using cycloheximide found that DAPK attenuates the proteasomal degradation of DDX20 protein, which is dependent on the kinase activity of DAPK. Our results shed light on new functions and regulation for both DAPK and DDX20 in carcinogenesis and identifies new potential therapeutic targets for HCC.
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Affiliation(s)
- Yide Huang
- Central Laboratory at The Second Affiliated Hospital of Fujian Traditional Chinese Medical UniversityCollaborative Innovation Center for Rehabilitation TechnologyFujian University of Traditional Chinese MedicineFuzhouChina
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Chenyi Wang
- Central Laboratory at The Second Affiliated Hospital of Fujian Traditional Chinese Medical UniversityCollaborative Innovation Center for Rehabilitation TechnologyFujian University of Traditional Chinese MedicineFuzhouChina
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Ke Li
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Yan Ye
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Aling Shen
- Fujian Key Laboratory of Integrative Medicine on GeriatricAcademy of Integrative MedicineFujian University of Traditional Chinese MedicineFuzhouChina
| | - Libin Guo
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Pengchen Chen
- Central Laboratory at The Second Affiliated Hospital of Fujian Traditional Chinese Medical UniversityCollaborative Innovation Center for Rehabilitation TechnologyFujian University of Traditional Chinese MedicineFuzhouChina
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Chen Meng
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Qingshui Wang
- Central Laboratory at The Second Affiliated Hospital of Fujian Traditional Chinese Medical UniversityCollaborative Innovation Center for Rehabilitation TechnologyFujian University of Traditional Chinese MedicineFuzhouChina
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Xinliu Yang
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Zhen Huang
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Xiaohua Xing
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian ProvinceMengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhouChina
| | - Youyu Lin
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian ProvinceMengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhouChina
| | - Jun Peng
- Fujian Key Laboratory of Integrative Medicine on GeriatricAcademy of Integrative MedicineFujian University of Traditional Chinese MedicineFuzhouChina
| | - Yao Lin
- Central Laboratory at The Second Affiliated Hospital of Fujian Traditional Chinese Medical UniversityCollaborative Innovation Center for Rehabilitation TechnologyFujian University of Traditional Chinese MedicineFuzhouChina
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of EducationCollege of Life SciencesFujian Normal UniversityFuzhouChina
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