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Wang F, Gui W, Rong M, Zhang L, Wu J, Li J, Wang R, Gouttia OG, Wang L, Yang X, Peng A. TOX High Mobility Group Box Family Member 4 Promotes DNA Double Strand Break Repair via Non-Homologous End Joining. J Biol Chem 2025:110174. [PMID: 40328361 DOI: 10.1016/j.jbc.2025.110174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 03/25/2025] [Accepted: 04/04/2025] [Indexed: 05/08/2025] Open
Abstract
Non-homologous end joining (NHEJ) is a pivotal mechanism in the repair of DNA double-strand breaks (DSBs). Central to NHEJ is the DNA-dependent protein kinase (DNA-PK) complex, comprising the KU heterodimer and the catalytic subunit, DNA-PKcs. In this study, we characterize TOX High Mobility Group Box Family Member 4 (TOX4) as a factor recruited to both laser-induced DNA damage and endonuclease-induced DNA DSBs. Depletion of TOX4 leads to accumulation of DNA damage, which is epistatic to DNA-PKcs. Consistently, TOX4 depletion substantially reduces NHEJ efficiency measured using both intrachromosomal and extrachromosomal repair assays. Our proteomic and biochemical analyses reveal TOX4 association with DNA-PK that is required for DNA-PKcs activation. Furthermore, we show that TOX4 coordinates with Phosphatase 1 Nuclear-Targeting Subunit (PNUTS) in NHEJ. PNUTS, previously shown to protect DNA-PKcs phosphorylation from protein phosphatase 1 (PP1)-mediated dephosphorylation, binds DNA-PK in a TOX4-dependent manner. In line with its role in DNA repair, TOX4 emerges as a promising target for anti-cancer drug development, and its targeting enhances tumor cell sensitivity to DNA damage in head and neck cancer and other malignancies.
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Affiliation(s)
- Feifei Wang
- Institute of Health Sciences and Technology, Institutes of Physical Sciences and Information Technology, Anhui University. Hefei, Anhui, China.
| | - Wenli Gui
- Institute of Health Sciences and Technology, Institutes of Physical Sciences and Information Technology, Anhui University. Hefei, Anhui, China
| | - Mengtao Rong
- Institute of Health Sciences and Technology, Institutes of Physical Sciences and Information Technology, Anhui University. Hefei, Anhui, China
| | - Liang Zhang
- Department of Orthopedics, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, P.R. China
| | - Jiajing Wu
- Institute of Health Sciences and Technology, Institutes of Physical Sciences and Information Technology, Anhui University. Hefei, Anhui, China
| | - Juan Li
- Institute of Health Sciences and Technology, Institutes of Physical Sciences and Information Technology, Anhui University. Hefei, Anhui, China
| | - Renqing Wang
- Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - Odjo G Gouttia
- Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill. Chapel Hill, NC, USA
| | - Ling Wang
- Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill. Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. Chapel Hill, NC, USA
| | - Xingyuan Yang
- Institute of Health Sciences and Technology, Institutes of Physical Sciences and Information Technology, Anhui University. Hefei, Anhui, China.
| | - Aimin Peng
- Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill. Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. Chapel Hill, NC, USA.
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Li X, Wang Z, Oakley G, Wang L, Lanzel E, Buchakjian M, Peng A. Targeting Aurora A to Overcome Cisplatin Resistance in Head and Neck Cancer. J Dent Res 2025; 104:531-540. [PMID: 40017056 PMCID: PMC12000625 DOI: 10.1177/00220345241309624] [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] [Indexed: 03/01/2025] Open
Abstract
Cisplatin-based chemotherapy is a cornerstone treatment for advanced recurrent head and neck squamous cell carcinoma (HNSCC). However, the effectiveness of the treatment is often hindered by intrinsic and acquired resistance and associated toxicity, highlighting a pressing unmet clinical need. Here, our compound screening identified Aurora kinase inhibitors, particularly those targeting Aurora A kinase, as potential agents to sensitize resistant HNSCC cells to cisplatin. While Aurora kinases are well-established regulators of mitosis, their precise role in cisplatin resistance is largely unknown, given that cisplatin confers toxicity primarily in cells undergoing DNA replication. We confirmed that depletion of Aurora A or its activators enhanced cisplatin response in resistant HNSCC cells. Analyses of a comprehensive database and locally treated HNSCC patient samples revealed compelling associations between Aurora A overexpression/activation and cisplatin resistance, tumor recurrence, and poor patient survival. Pharmacologic inhibition of Aurora A effectively synergized with cisplatin treatment in cellular assays and a syngeneic mouse tumor model of HNSCC. Mechanistically, Aurora A inhibition enhanced apoptosis induction after cisplatin treatment, particularly in S-phase cells; induced replication stress; and suppressed the repair of cisplatin-induced DNA crosslinking. Taken together, our findings shed light on important functions of Aurora A kinase beyond mitotic regulation. The multifaceted roles of Aurora A suggest its potential as a prime anticancer drug target. Given the ongoing investigations into numerous Aurora inhibitors for cancer therapy, exploring their clinical applications in HNSCC, especially in combination with platinum drugs, may hold significant promise.
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Affiliation(s)
- X. Li
- Department of Biomedical Sciences, Adams School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Z. Wang
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, NE, USA
| | - G.G. Oakley
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, NE, USA
| | - L. Wang
- Department of Biomedical Sciences, Adams School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - E.A. Lanzel
- Department of Oral Pathology, Radiology, & Medicine, College of Dentistry, The University of Iowa, Iowa City, IA, USA
| | - M.R. Buchakjian
- Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals & Clinics, Iowa City, IA, USA
| | - A. Peng
- Department of Biomedical Sciences, Adams School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NA, USA
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Fung AKY, Chok KSH. Hepatic artery infusion chemotherapy: A resurgence. World J Gastrointest Oncol 2025; 17:99612. [PMID: 39958544 PMCID: PMC11755999 DOI: 10.4251/wjgo.v17.i2.99612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 10/31/2024] [Accepted: 11/25/2024] [Indexed: 01/18/2025] Open
Abstract
In this manuscript, we comment on the article by Zhou et al, who assessed the efficacy of hepatic arterial infusion chemotherapy (HAIC) and its combination strategies for advanced hepatocellular carcinoma (HCC) using network meta-analysis methodology. We focus specifically on the potential advantages and role of HAIC in the treatment algorithm for advanced HCC. However, there remains numerous knowledge gaps before the role of HAIC can be established. There is significant heterogeneity of HAIC regimes with difficult interpretation of the clinical outcomes. Additionally, there is a lack of direct comparative data between HAIC, systemic chemotherapy, novel immunotherapies and targeted therapies. The underlying biochemical mechanisms that might explain the efficacy of HAIC and its effect on the HCC microenvironment requires further research. In the developing era of nanotechnology and targeted drug delivery systems, there is potential for integration of HAIC with novel technologies to effectively treat advanced HCC whilst minimising systemic complications.
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Affiliation(s)
- Andrew Kai-Yip Fung
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
| | - Kenneth Siu Ho Chok
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
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Mohammadi F, Nejatollahi M, Sheikhnia F, Ebrahimi Y, Mohammadi M, Rashidi V, Alizadeh-Fanalou S, Azizzadeh B, Majidinia M. MiRNAs: main players of cancer drug resistance target ABC transporters. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-024-03719-y. [PMID: 39808313 DOI: 10.1007/s00210-024-03719-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/08/2024] [Indexed: 01/16/2025]
Abstract
Chemotherapy remains the cornerstone of cancer treatment; however, its efficacy is frequently compromised by the development of chemoresistance. Multidrug resistance (MDR), characterized by the refractoriness of cancer cells to a wide array of chemotherapeutic agents, presents a significant barrier to achieving successful and sustained cancer remission. One critical factor contributing to this chemoresistance is the overexpression of ATP-binding cassette (ABC) transporters. Furthermore, additional mechanisms, such as the malfunctioning of apoptosis, alterations in DNA repair systems, and resistance mechanisms inherent to cancer stem cells, exacerbate the issue. Intriguingly, microRNAs (miRNAs) have demonstrated potential in modulating chemoresistance by specifically targeting ABC transporters, thereby offering promising new avenues for overcoming drug resistance. This narrative review aims to elucidate the molecular underpinnings of drug resistance, with a particular focus on the roles of ABC transporters and the regulatory influence of miRNAs on these transporters.
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Affiliation(s)
- Forogh Mohammadi
- Department of Veterinary, Agriculture Faculty, Kermanshah Branch, Islamic Azad University, Kermanshah, Iran
| | - Masoumeh Nejatollahi
- Research Center for High School Students, Education System Zanjan Province, Zanjan, Iran
| | - Farhad Sheikhnia
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yaser Ebrahimi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mahya Mohammadi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Rashidi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Shahin Alizadeh-Fanalou
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Bita Azizzadeh
- Department of Biochemistry, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
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Zhang S, Dou T, Li H, Yu H, Zhang W, Sun L, Yang J, Wang Z, Yang H. Knockdown of IGF2BP2 overcomes cisplatin-resistance in lung cancer through downregulating Spon2 gene. Hereditas 2024; 161:55. [PMID: 39731162 DOI: 10.1186/s41065-024-00360-w] [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: 07/09/2024] [Accepted: 12/20/2024] [Indexed: 12/29/2024] Open
Abstract
BACKGROUND Cisplatin (DDP) resistance has long posed a challenge in the clinical treatment of lung cancer (LC). Insulin-like growth factor 2 binding protein 2 (IGF2BP2) has been identified as an oncogenic factor in LC, whereas its specific role in DDP resistance in LC remains unclear. RESULTS In this study, we investigated the role of IGF2BP2 on DDP resistance in DDP-resistant A549 cells (A549/DDP) in vitro and in a DDP-resistant lung tumor-bearing mouse model in vivo. Additionally, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted to identify the potential mRNAs regulated by IGF2BP2, an N6-methyladenosine (m6A) regulator, in the tumor tissues of mice. Compared to normal tissues, IGF2BP2 levels were increased in LC tissues and in relapsed/resistant LC tissues. Most importantly, IGF2BP2 levels were significantly higher in relapsed/resistant LC tissues than in LC tissues. Significantly, knockdown of IGF2BP2 or DDP treatment inhibited A549 cell viability, migration, and cell cycle progression. Consistently, DDP treatment suppressed the viability and migration and triggered cell cycle arrest in A549/DDP cells in vitro, as well as reduced tumor volume and weight of A549/DDP tumor-bearing mice; meanwhile, the combination of DDP and IGF2BP2 siRNA further significantly inhibited A549/DDP cell growth in vitro and in vivo compared to DDP treatment alone. Furthermore, MeRIP-seq data showed that IGF2BP2 downregulation remarkably elevated m6A levels of spondin 2 (Spon2) and reduced mRNA levels of Spon2 in tumor tissues from A549 tumor-bearing mice. Meanwhile, the combination of DDP and IGF2BP2 siRNA notably reduced Spon2 levels, as well as inhibited the viability and induced apoptosis in A549/DDP cells; however, these effects were reversed by Spon2 overexpression. CONCLUSION Collectively, downregulation of IGF2BP2 could overcome DDP resistance in LC through declining the Spon2 gene expression in an m6A-dependent manner. These results may provide a new strategy for overcoming DDP resistance in LC.
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Affiliation(s)
- Shilei Zhang
- Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
- Key Laboratoy of Radiation Physics and Biology of Inner, Mongolia Medical University, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
- Department of Oncology, Xilingol League Central Hospital, Xilingol, 026000, China
| | - Ting Dou
- Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
- Key Laboratoy of Radiation Physics and Biology of Inner, Mongolia Medical University, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
- Department of Graduate School, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, 010020, China
| | - Hong Li
- Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
- Key Laboratoy of Radiation Physics and Biology of Inner, Mongolia Medical University, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
| | - Hongfang Yu
- Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
- Key Laboratoy of Radiation Physics and Biology of Inner, Mongolia Medical University, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
| | - Wei Zhang
- Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
- Key Laboratoy of Radiation Physics and Biology of Inner, Mongolia Medical University, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
| | - Liping Sun
- Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
- Key Laboratoy of Radiation Physics and Biology of Inner, Mongolia Medical University, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
| | - Jingwen Yang
- Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
- Key Laboratoy of Radiation Physics and Biology of Inner, Mongolia Medical University, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China
| | - Zhenfei Wang
- The Laboratory for Tumor Molecular Diagnosis, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China.
| | - Hao Yang
- Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China.
- Key Laboratoy of Radiation Physics and Biology of Inner, Mongolia Medical University, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, Hohhot, 010020, China.
- Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Autonomous Region, No. 42, Zhaowuda Road, Saihan District, Hohhot, 010000, China.
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Palollathil A, Nandakumar R, Ahmed M, Velikkakath AKG, Nisar M, Nisar M, Devasahayam Arokia Balaya R, Parate SS, Hanehalli V, Mahin A, Mathew RT, Shetty R, Codi JAK, Revikumar A, Vijayakumar M, Prasad TSK, Raju R. HNCDrugResDb: a platform for deciphering drug resistance in head and neck cancers. Sci Rep 2024; 14:25327. [PMID: 39455682 PMCID: PMC11511878 DOI: 10.1038/s41598-024-75861-9] [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: 05/11/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Drug resistance poses a significant obstacle to the success of anti-cancer therapy in head and neck cancers (HNCs). We aim to develop a platform for visualizing and analyzing molecular expression alterations associated with HNC drug resistance. Through data mining, we convened differentially expressed molecules and context-specific signaling events involved in drug resistance. The driver genes, interaction networks and transcriptional regulations were explored using bioinformatics approaches. A total of 2364 differentially expressed molecules were identified in 78 distinct drug-resistant cells against 14 anti-cancer drugs, comprising 1131 mRNAs, 746 proteins, 62 lncRNAs, 257 miRNAs, 1 circRNA, and 166 post-translational modifications. Among these, 255 molecules were considerably, the signature driver genes of HNC drug resistance. Further, we also developed a landscape of signaling pathways and their cross-talk with diverse signaling modules involved in drug resistance. Additionally, a publicly-accessible database named "HNCDrugResDb" was designed with browse, query, and pathway explorer options to fetch and enrich molecular alterations and signaling pathways altered in drug resistance. HNCDrugResDb is also enabled with a Drug Resistance Analysis tool as an initial platform to infer the likelihood of resistance based on the expression pattern of driver genes. HNCDrugResDb is anticipated to have substantial implications for future advancements in drug discovery and optimization of personalized medicine approaches.
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Affiliation(s)
- Akhina Palollathil
- Center for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
| | - Revathy Nandakumar
- Center for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
- Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
| | - Mukhtar Ahmed
- Department of Zoology, College of Science, King Saud University, Kingdom of Saudi Arabia, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
| | - Anoop Kumar G Velikkakath
- Center for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India.
| | - Mahammad Nisar
- Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
| | - Muhammad Nisar
- Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
| | - Rex Devasahayam Arokia Balaya
- Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
| | - Sakshi Sanjay Parate
- Center for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
| | - Vidyarashmi Hanehalli
- School of Biology, Indian Institute of Science Education and Research, Thiruvananthapuram, Kerala, 695551, India
| | - Althaf Mahin
- Center for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
- Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
| | - Rohan Thomas Mathew
- Department of Surgical Oncology, Yenepoya Medical College, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
| | - Rohan Shetty
- Department of Surgical Oncology, Yenepoya Medical College, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
| | - Jalaluddin Akbar Kandel Codi
- Department of Surgical Oncology, Yenepoya Medical College, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
| | - Amjesh Revikumar
- Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India
- Kerala Genome Data Centre, Kerala Development and Innovation Strategic Council, Vazhuthacaud, Thiruvananthapuram, Kerala, 695014, India
| | - Manavalan Vijayakumar
- Department of Surgical Oncology, Yenepoya Medical College, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India.
| | - Thottethodi Subrahmanya Keshava Prasad
- Center for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India.
| | - Rajesh Raju
- Center for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India.
- Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University), Mangalore, Karnataka, 575018, India.
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Splichal RC, Chen K, Walton SP, Chan C. The Role of Endoplasmic Reticulum Stress on Reducing Recombinant Protein Production in Mammalian Cells. Biochem Eng J 2024; 210:109434. [PMID: 39220803 PMCID: PMC11360842 DOI: 10.1016/j.bej.2024.109434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Therapeutic recombinant protein production relies on industrial scale culture of mammalian cells to produce active proteins in quantities sufficient for clinical use. The combination of stresses from industrial cell culture environment and recombinant protein production can overwhelm the protein synthesis machinery in the endoplasmic reticulum (ER). This leads to a buildup of improperly folded proteins which induces ER stress. Cells respond to ER stress by activating the Unfolded Protein Response (UPR). To restore proteostasis, ER sensor proteins reduce global protein synthesis and increase chaperone protein synthesis, and if that is insufficient the proteins are degraded. If proteostasis is still not restored, apoptosis is initiated. Increasing evidence suggests crosstalk between ER proteostasis and DNA damage repair (DDR) pathways. External factors (e.g., metabolites) from the cellular environment as well as internal factors (e.g., transgene copy number) can impact genome stability. Failure to maintain genome integrity reduces cell viability and in turn protein production. This review focuses on the association between ER stress and processes that affect protein production and secretion. The processes mediated by ER stress, including inhibition of global protein translation, chaperone protein production, degradation of misfolded proteins, DNA repair, and protein secretion, impact recombinant protein production. Recombinant protein production can be reduced by ER stress through increased autophagy and protein degradation, reduced protein secretion, and reduced DDR response.
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Affiliation(s)
- R. Chauncey Splichal
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
| | - Kevin Chen
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
| | - S. Patrick Walton
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
| | - Christina Chan
- Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA
- Department of Biochemistry and Molecular Biology, Michigan State University, MI, USA
- Department of Computer Science and Engineering, Michigan State University, MI, USA
- Institute for Quantitative Health Science and Engineering, Division of Medical Devices, Michigan State University, MI, USA
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8
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Lee JH. Targeting the ATM pathway in cancer: Opportunities, challenges and personalized therapeutic strategies. Cancer Treat Rev 2024; 129:102808. [PMID: 39106770 DOI: 10.1016/j.ctrv.2024.102808] [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: 06/25/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 08/09/2024]
Abstract
Ataxia telangiectasia mutated (ATM) kinase plays a pivotal role in orchestrating the DNA damage response, maintaining genomic stability, and regulating various cellular processes. This review provides a comprehensive analysis of ATM's structure, activation mechanisms, and various functions in cancer development, progression, and treatment. I discuss ATM's dual nature as both a tumor suppressor and potential promoter of cancer cell survival in certain contexts. The article explores the complex signaling pathways mediated by ATM, its interactions with other DNA repair mechanisms, and its influence on cell cycle checkpoints, apoptosis, and metabolism. I examine the clinical implications of ATM alterations, including their impact on cancer predisposition, prognosis, and treatment response. The review highlights recent advances in ATM-targeted therapies, discussing ongoing clinical trials of ATM inhibitors and their potential in combination with other treatment modalities. I also address the challenges in developing effective biomarkers for ATM activity and patient selection strategies for personalized cancer therapy. Finally, I outline future research directions, emphasizing the need for refined biomarker development, optimized combination therapies, and strategies to overcome potential resistance mechanisms. This comprehensive overview underscores the critical importance of ATM in cancer biology and its emerging potential as a therapeutic target in precision oncology.
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Affiliation(s)
- Ji-Hoon Lee
- Department of Biological Sciences, Research Center of Ecomimetics, Chonnam National University, Gwangju 61186, Republic of Korea.
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9
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Kiri S, Ryba T. Cancer, metastasis, and the epigenome. Mol Cancer 2024; 23:154. [PMID: 39095874 PMCID: PMC11295362 DOI: 10.1186/s12943-024-02069-w] [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: 04/30/2024] [Accepted: 07/22/2024] [Indexed: 08/04/2024] Open
Abstract
Cancer is the second leading cause of death worldwide and disease burden is expected to increase globally throughout the next several decades, with the majority of cancer-related deaths occurring in metastatic disease. Cancers exhibit known hallmarks that endow them with increased survival and proliferative capacities, frequently as a result of de-stabilizing mutations. However, the genomic features that resolve metastatic clones from primary tumors are not yet well-characterized, as no mutational landscape has been identified as predictive of metastasis. Further, many cancers exhibit no known mutation signature. This suggests a larger role for non-mutational genome re-organization in promoting cancer evolution and dissemination. In this review, we highlight current critical needs for understanding cell state transitions and clonal selection advantages for metastatic cancer cells. We examine links between epigenetic states, genome structure, and misregulation of tumor suppressors and oncogenes, and discuss how recent technologies for understanding domain-scale regulation have been leveraged for a more complete picture of oncogenic and metastatic potential.
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Affiliation(s)
- Saurav Kiri
- College of Medicine, University of Central Florida, 6850 Lake Nona Blvd., Orlando, 32827, Florida, USA.
| | - Tyrone Ryba
- Department of Natural Sciences, New College of Florida, 5800 Bay Shore Rd., Sarasota, 34243, Florida, USA.
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10
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Sa P, Singh P, Panda S, Swain RK, Dash R, Sahoo SK. Reversal of cisplatin resistance in oral squamous cell carcinoma by piperlongumine loaded smart nanoparticles through inhibition of Hippo-YAP signaling pathway. Transl Res 2024; 268:63-78. [PMID: 38499286 DOI: 10.1016/j.trsl.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 02/13/2024] [Accepted: 03/07/2024] [Indexed: 03/20/2024]
Abstract
Cisplatin alone or in combination with 5FU and docetaxel is the preferred chemotherapy regimen for advanced-stage OSCC patients. However, its use has been linked to recurrence and metastasis due to the development of drug resistance. Therefore, sensitization of cancer cells to conventional chemotherapeutics can be an effective strategy to overcome drug resistance. Piperlongumine (PL), an alkaloid, have shown anticancer properties and sensitizes numerous neoplasms, but its effect on OSCC has not been explored. However, low aqueous solubility and poor pharmacokinetics limit its clinical application. Therefore, to improve its therapeutic efficacy, we developed piperlongumine-loaded PLGA-based smart nanoparticles (smart PL-NPs) that can rapidly release PL in an acidic environment of cancer cells and provide optimum drug concentrations to overcome chemoresistance. Our results revealed that smart PL-NPs has high cellular uptake in acidic environment, facilitating the intracellular delivery of PL and sensitizing cancer cells to cisplatin, resulting in synergistic anticancer activity in vitro by increasing DNA damage, apoptosis, and inhibiting drug efflux. Further, we have mechanistically explored the Hippo-YAP signaling pathway, which is the critical mediator of chemoresistance, and investigated the chemosensitizing effect of PL in OSCC. We observed that PL alone and in combination with cisplatin significantly inhibits the activation of YAP and its downstream target genes and proteins. In addition, the combination of cisplatin with smart PL-NPs significantly inhibited tumor growth in two preclinical models (patient-derived cell based nude mice and zebrafish xenograft). Taken together, our findings suggest that smart PL-NPs with cisplatin will be a novel formulation to reverse cisplatin resistance in patients with advanced OSCC.
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Affiliation(s)
- Pratikshya Sa
- Institute of Life Sciences, Nalco square, Chandrasekharpur, Bhubaneswar, Odisha 751 023, India; Regional Centre for Biotechnology, Faridabad-Gurgaon Expressway, Faridabad, Haryana 121 001, India
| | - Priya Singh
- Institute of Life Sciences, Nalco square, Chandrasekharpur, Bhubaneswar, Odisha 751 023, India; Regional Centre for Biotechnology, Faridabad-Gurgaon Expressway, Faridabad, Haryana 121 001, India
| | - Sudhakar Panda
- Institute of Life Sciences, Nalco square, Chandrasekharpur, Bhubaneswar, Odisha 751 023, India
| | - Rajeeb K Swain
- Institute of Life Sciences, Nalco square, Chandrasekharpur, Bhubaneswar, Odisha 751 023, India
| | - Rupesh Dash
- Institute of Life Sciences, Nalco square, Chandrasekharpur, Bhubaneswar, Odisha 751 023, India
| | - Sanjeeb Kumar Sahoo
- Institute of Life Sciences, Nalco square, Chandrasekharpur, Bhubaneswar, Odisha 751 023, India.
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11
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Zhou Q, Tu X, Hou X, Yu J, Zhao F, Huang J, Kloeber J, Olson A, Gao M, Luo K, Zhu S, Wu Z, Zhang Y, Sun C, Zeng X, Schoolmeester KJ, Weroha JS, Hu X, Jiang Y, Wang L, Mutter RW, Lou Z. Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy. Drug Resist Updat 2024; 74:101085. [PMID: 38636338 PMCID: PMC11095636 DOI: 10.1016/j.drup.2024.101085] [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: 09/27/2023] [Revised: 04/03/2024] [Accepted: 04/08/2024] [Indexed: 04/20/2024]
Abstract
Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged for its regulatory roles in immune cell function, cell adhesion, and vascular development. This study presents evidence indicating that Syk expression in high-grade serous ovarian cancer and triple-negative breast cancers promotes DNA double-strand break resection, homologous recombination (HR), and subsequent therapeutic resistance. Our investigations reveal that Syk is activated by ATM following DNA damage and is recruited to DNA double-strand breaks by NBS1. Once localized to the break site, Syk phosphorylates CtIP, a pivotal mediator of resection and HR, at Thr-847 to promote repair activity, particularly in Syk-expressing cancer cells. Inhibition of Syk or its genetic deletion impedes CtIP Thr-847 phosphorylation and overcomes the resistant phenotype. Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.
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Affiliation(s)
- Qin Zhou
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Xinyi Tu
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Xiaonan Hou
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Jia Yu
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States
| | - Fei Zhao
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Jinzhou Huang
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Jake Kloeber
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Anna Olson
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Ming Gao
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Kuntian Luo
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Shouhai Zhu
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Zheming Wu
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Yong Zhang
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Chenyu Sun
- AMITA Health Saint Joseph Hospital Chicago, Chicago, IL 60657, United States
| | - Xiangyu Zeng
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | | | - John S Weroha
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Xiwen Hu
- Nursing Department, Rochester Community and Technical College, Rochester, MN 55904, United States
| | - Yanxia Jiang
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Liewei Wang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States
| | - Robert W Mutter
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, United States; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States.
| | - Zhenkun Lou
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, United States; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States.
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12
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Elkoshi N, Parikh S, Malcov-Brog H, Parikh R, Manich P, Netti F, Maliah A, Elkoshi H, Haj M, Rippin I, Frand J, Perluk T, Haiat-Factor R, Golan T, Regev-Rudzki N, Kiper E, Brenner R, Gonen P, Dror I, Levi H, Hameiri O, Cohen-Gulkar M, Eldar-Finkelman H, Ast G, Nizri E, Ziv Y, Elkon R, Khaled M, Ebenstein Y, Shiloh Y, Levy C. Ataxia Telangiectasia Mutated Signaling Delays Skin Pigmentation upon UV Exposure by Mediating MITF Function toward DNA Repair Mode. J Invest Dermatol 2023; 143:2494-2506.e4. [PMID: 37236596 DOI: 10.1016/j.jid.2023.03.1686] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 02/24/2023] [Accepted: 03/02/2023] [Indexed: 05/28/2023]
Abstract
Skin pigmentation is paused after sun exposure; however, the mechanism behind this pausing is unknown. In this study, we found that the UVB-induced DNA repair system, led by the ataxia telangiectasia mutated (ATM) protein kinase, represses MITF transcriptional activity of pigmentation genes while placing MITF in DNA repair mode, thus directly inhibiting pigment production. Phosphoproteomics analysis revealed ATM to be the most significantly enriched pathway among all UVB-induced DNA repair systems. ATM inhibition in mouse or human skin, either genetically or chemically, induces pigmentation. Upon UVB exposure, MITF transcriptional activation is blocked owing to ATM-dependent phosphorylation of MITF on S414, which modifies MITF activity and interactome toward DNA repair, including binding to TRIM28 and RBBP4. Accordingly, MITF genome occupancy is enriched in sites of high DNA damage that are likely repaired. This suggests that ATM harnesses the pigmentation key activator for the necessary rapid, efficient DNA repair, thus optimizing the chances of the cell surviving. Data are available from ProteomeXchange with the identifier PXD041121.
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Affiliation(s)
- Nadav Elkoshi
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shivang Parikh
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hagar Malcov-Brog
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Roma Parikh
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Paulee Manich
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Francesca Netti
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Avishai Maliah
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hana Elkoshi
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Majd Haj
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ido Rippin
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jacob Frand
- Department of Plastic and Reconstructive Surgery, Edith Wolfson Medical Center, Holon, Israel
| | - Tomer Perluk
- Department of Plastic and Reconstructive Surgery, Edith Wolfson Medical Center, Holon, Israel
| | - Rivi Haiat-Factor
- Department of Plastic and Reconstructive Surgery, Edith Wolfson Medical Center, Holon, Israel
| | - Tamar Golan
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Neta Regev-Rudzki
- Department of Biomolecular Sciences, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel
| | - Edo Kiper
- Department of Biomolecular Sciences, Faculty of Biochemistry, Weizmann Institute of Science, Rehovot, Israel
| | - Ronen Brenner
- Institute of Oncology, Edith Wolfson Medical Center, Holon, Israel
| | - Pinchas Gonen
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Iris Dror
- Department of Biological Chemistry, University of California Loss Angeles School of Medicine, Los Angeles, California, USA
| | - Hagai Levi
- The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel
| | - Ofir Hameiri
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Mazal Cohen-Gulkar
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hagit Eldar-Finkelman
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gil Ast
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eran Nizri
- Department of Dermatology, Tel Aviv Sourasky Medical Center Ichilov, Tel Aviv, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Ziv
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Rani Elkon
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Mehdi Khaled
- INSERM 1186, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Yuval Ebenstein
- School of Chemistry, Center for Nanoscience and Nanotechnology, Center for Light-Matter Interaction, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Yosef Shiloh
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Carmit Levy
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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13
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Dewenter I, Kumbrink J, Poxleitner P, Smolka W, Liokatis P, Fliefel R, Otto S, Obermeier KT. New insights into redox-related risk factors and therapeutic targets in oral squamous cell carcinoma. Oral Oncol 2023; 147:106573. [PMID: 37951115 DOI: 10.1016/j.oraloncology.2023.106573] [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: 06/20/2023] [Revised: 09/13/2023] [Accepted: 09/18/2023] [Indexed: 11/13/2023]
Abstract
Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral cavity accounting for 90 % of oral cancer with a global incidence of 350.000 new cases per year. Curative resection along with adjuvant radiation therapy or a combination of radiotherapy with chemotherapy remain as gold standard in treating OSCC. Still, local recurrence, lymph nodal recurrence, and complications of radiation remain the main cause of tumor-related mortality. Reactive oxygen species are not only correlated to the etiology of OSCC due to oxidative DNA damage, lipid peroxidation or effecting signal transduction cascades that effect cell proliferation and tumorigenesis, but are also of great interest in the therapy of OSCC patients. As induced oxidative stress can be used therapeutically for the induction of tumor cell death, redox targets might be a therapeutic addition to the conventional treatment options. In this review, we discuss markers of impaired redox homeostasis as well as potential redox-related treatment targets in OSCC.
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Affiliation(s)
- Ina Dewenter
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, University Hospital, Ludwig Maximilians University, 80337 Munich, Germany.
| | - Joerg Kumbrink
- Institute of Pathology, Faculty of Medicine, Ludwig Maximilians University, Munich, Germany
| | - Philipp Poxleitner
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, University Hospital, Ludwig Maximilians University, 80337 Munich, Germany
| | - Wenko Smolka
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, University Hospital, Ludwig Maximilians University, 80337 Munich, Germany
| | - Paris Liokatis
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, University Hospital, Ludwig Maximilians University, 80337 Munich, Germany
| | - Riham Fliefel
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, University Hospital, Ludwig Maximilians University, 80337 Munich, Germany
| | - Sven Otto
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, University Hospital, Ludwig Maximilians University, 80337 Munich, Germany
| | - Katharina Theresa Obermeier
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, University Hospital, Ludwig Maximilians University, 80337 Munich, Germany
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14
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Sekar V, Veerabathiran R, Pandian A, Sivamani G. Targeting liver cancer stem cell through EpCAM therapy targeted with chemotherapy endorse enhanced progression in hepatocellular carcinoma. EGYPTIAN LIVER JOURNAL 2023; 13:29. [DOI: 10.1186/s43066-023-00263-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 05/29/2023] [Indexed: 12/07/2023] Open
Abstract
Abstract
Background
Two chief hurdles in most cancer treatments are chemoresistance and tumor recurrence, especially counting hepatocellular carcinoma (HCC). Most conformist chemotherapy fails to completely cure HCC patients because of its susceptibility to develop multidrug resistance (MDR) through factors such as hypoxia, cancer stem cells, and drug efflux mechanism cancer stem cells (CSC) which are significant factors involved in chemoresistance. It has been exposed that targeting liver cancer stem cells and chemotherapeutic drugs have a better selected, overall survival rate for hepatocellular carcinoma patients.
Aim
This study aims to investigate the effectiveness of targeting stem cells for liver cancer using a therapy that targets EpCAM in combination with chemotherapy and how this approach can enhance the treatment outcomes in hepatocellular carcinoma, the most prevalent kind of liver cancer.
Results
The outcome was studied by flow cytometry, Western blot, RT-PCR, and cytotoxicity assays. EpCAM gene silenced and XAV939-treated cells showed decreased expression of CD133, a liver cancer stem cell (LCSC) marker in flow cytometry analysis, and reduced expression of ABCG2 gene, which is a reliable marker for chemoresistance in RT-PCR and western blot analysis; it was also unable to form colonies in colony forming assay. Similarly, in the spheroid formation assay, EpCAM gene silenced cells and XAV939-treated cells in combinations with cisplatin treatment were powerless to appear spheroid, whereas cisplatin alone-treated cells showed spheroids. In the cytotoxicity assay, cisplatin alone and combined with EpCAM silenced and XAV939-treated cells showed more lactate dehydrogenase (LDH) release than EpCAM silenced arm XAV939 treated components.
Conclusion
These findings confirm our hypothesis that conventional chemotherapy kills cancer cells but not cancer stem cells. We believe EpCAM-targeted therapy enhances chemosensitivity and decreases relapsed chances. This approach might be the best option for a better prognosis for hepatocellular carcinoma patients.
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15
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Zhou Q, Tu X, Hou X, Yu J, Zhao F, Huang J, Kloeber J, Olson A, Gao M, Luo K, Zhu S, Wu Z, Zhang Y, Sun C, Zeng X, Schoolmeester K, Weroha J, Wang L, Mutter R, Lou Z. Syk-dependent alternative homologous recombination activation promotes cancer resistance to DNA targeted therapy. RESEARCH SQUARE 2023:rs.3.rs-2922520. [PMID: 37333340 PMCID: PMC10275042 DOI: 10.21203/rs.3.rs-2922520/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase known to regulate immune cell function, cell adhesion, and vascular development. Here, we report that Syk can be expressed in high grade serous ovarian cancer and triple negative breast cancers and promotes DNA double strand break resection, homologous recombination (HR) and therapeutic resistance. We found that Syk is activated by ATM following DNA damage and is recruited to DNA double strand breaks by NBS1. Once at the break site, Syk phosphorylates CtIP, a key mediator of resection and HR, at Thr-847 to promote repair activity, specifically in Syk expressing cancer cells. Syk inhibition or genetic deletion abolished CtIP Thr-847 phosphorylation and overcame the resistant phenotype. Collectively, our findings suggest that Syk drives therapeutic resistance by promoting DNA resection and HR through a novel ATM-Syk-CtIP pathway, and that Syk is a new tumor-specific target to sensitize Syk-expressing tumors to PARPi and other DNA targeted therapy.
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Affiliation(s)
- Qin Zhou
- Department of Radiation Oncology, Mayo Clinic
| | - Xinyi Tu
- Department of Radiation Oncology, Mayo Clinic
| | | | - Jia Yu
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
| | - Fei Zhao
- Department of Oncology, Mayo Clinic
| | | | | | | | - Ming Gao
- Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences
| | | | | | | | | | | | | | | | | | - Liewei Wang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
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16
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Biswal S, Panda M, Sahoo RK, Tripathi SK, Biswal BK. Tumour microenvironment and aberrant signaling pathways in cisplatin resistance and strategies to overcome in oral cancer. Arch Oral Biol 2023; 151:105697. [PMID: 37079976 DOI: 10.1016/j.archoralbio.2023.105697] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/07/2023] [Accepted: 04/12/2023] [Indexed: 04/22/2023]
Abstract
OBJECTIVE Oral cancer is the sixteenth most prevalent cancer in the world and the third-most in India. Despite of several treatment modalities, the cure rate of oral cancer is still low due to drug resistance mechanisms, which are caused by many reasons. It is necessary to improve the existing treatment strategies and discover neoteric therapy to kill cancer cells, which will give oral cancer's cure rate more success. So this review aims to delineate the molecular mechanisms behind cisplatin resistance, specifically the role of the tumor microenvironment, extracellular vesicles, and altered signaling pathways and its overcoming strategies in oral cancer. DESIGN This review was designed by searching words like cancer, oral cancer, cisplatin-resistance, tumor microenvironment, aberrant signalings, and extracellular vesicles, overcoming strategies for cisplatin resistance in databases like PubMed, Google Scholar, web science, and Scopus. Data available in this review is from 2017 to 2021. RESULTS After searching too much data, we found these 98 data appropriate for our review. From these data, we found that tumor microenvironment, extracellular vesicles, and altered signaling pathways like PI3K/AKT, EGFR, NOTCH, Ras, PTEN, Nf-κβ, and Wnt signaling have a crucial role in resistance development towards cisplatin in oral cancer. CONCLUSIONS Lastly, this review explores the alternative strategies to overcome cisplatin resistance likely, the combination therapy and targeted therapy by combining more than one chemotherapeutic drug or inhibitors of signaling pathways and also by using nanoparticle loaded drugs that will reduce the drug efflux, which gives new treatment strategies.
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Affiliation(s)
- Stuti Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Munmun Panda
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Rajeev K Sahoo
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Surya Kant Tripathi
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Bijesh K Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India.
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17
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Li J, Wang L, Sun Y, Wang Z, Qian Y, Duraisamy V, Antary TMA. Zerumbone-induced reactive oxygen species-mediated oxidative stress re-sensitizes breast cancer cells to paclitaxel. Biotechnol Appl Biochem 2023; 70:28-37. [PMID: 35240000 DOI: 10.1002/bab.2326] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 01/21/2022] [Indexed: 12/24/2022]
Abstract
Chemotherapy is an effective approach for cancer therapy when plant-derived sensitizers are combined with chemotherapeutics. Zerumbone, a natural phytochemical, has been documented to have various pharmacological roles. Here, we evaluated the chemosensitization potential of zerumbone in a breast cancer cell line in vitro. Zerumbone-induced cytotoxicity in MCF-7 cells was assessed by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT)-based metabolic analysis. Reactive oxygen species (ROS)-mediated mitochondrial membrane alterations, DNA damage, and apoptotic morphological changes were measured by fluorescence microscopy methods. A biochemical assay was employed to analyze Thiobarbituric acid reactive substances (TBARS) and antioxidant levels. Apoptotic marker expression levels were investigated by immunoblotting. MTT assay revealed that zerumbone significantly enhanced paclitaxel (PTX)-induced cell death in breast cancer cells in a concentration-dependent manner. Furthermore, our study demonstrated that zerumbone (15 μM) significantly enhanced ROS when combined with PTX (1 μM) treatment. Additionally, we observed that zerumbone enhanced the impairment of mitochondrial membrane potential and oxidative DNA damage, thereby inducing apoptosis in combination with PTX. Western blot analysis indicated that zerumbone significantly upregulated BAX, caspase-7, and caspase-9 expression and decreased BCL-2 expression, thereby inducing proapoptotic protein-mediated cell death combined with PTX. The prooxidant properties of zerumbone potentially resensitize breast cancer cells to PTX by enhancing intracellular ROS-mediated oxidative stress.
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Affiliation(s)
- Jutao Li
- Breast and Thyroid Surgery Ward 1, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, China
| | - Lingying Wang
- Department of Thoracic Surgery, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, Hubei, China
| | - Yuxin Sun
- Department of Obstetrics and Gynecology, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, China
| | - Zhe Wang
- Department of Pharmacy Medical Guarantee Center, PLA General Hospital in The Fourth Medical Center, Beijing, China
| | - Ye Qian
- Department of Oncology, Affiliated Hai 'an Hospital of Nantong University, Haian, Jiangsu, 226600, China
| | | | - Tawfiq M Al Antary
- Pesticide and Economic Entomology, Faculty of Agriculture, the University of Jordan, Amman, Jordan
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Gouttia OG, Zhao J, Li Y, Zwiener MJ, Wang L, Oakley GG, Peng A. The MASTL-ENSA-PP2A/B55 axis modulates cisplatin resistance in oral squamous cell carcinoma. Front Cell Dev Biol 2022; 10:904719. [PMID: 36247015 PMCID: PMC9554306 DOI: 10.3389/fcell.2022.904719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 08/31/2022] [Indexed: 02/01/2023] Open
Abstract
Platinum-based chemotherapy is the standard first-line treatment for oral squamous cell carcinoma (OSCC) that is inoperable, recurrent, or metastatic. Platinum sensitivity is a major determinant of patient survival in advanced OSCC. Here, we investigated the involvement of MASTL, a cell cycle kinase that mediates ENSA/ARPP19 phosphorylation and PP2A/B55 inhibition, in OSCC therapy. Interestingly, upregulation of MASTL and ENSA/ARPP19, and downregulation of PP2A/B55, were common in OSCC. MASTL expression was in association with poor patient survival. In established OSCC cell lines, upregulation of MASTL and ENSA, and downregulation of B55 genes, correlated with cisplatin resistance. We further confirmed that stable expression of MASTL in OSCC cells promoted cell survival and proliferation under cisplatin treatment, in an ENSA-dependent manner. Conversely, deletion of MASTL or ENSA, or overexpression of B55α, sensitized cisplatin response, consistent with increased DNA damage accumulation, signaling, and caspase activation. Moreover, GKI-1, the first-in-class small molecule inhibitor of MASTL kinase, phenocopied MASTL depletion in enhancing the outcome of cisplatin treatment in OSCC cells, at a dose substantially lower than that needed to disrupt mitotic entry. Finally, GKI-1 exhibited promising efficacy in a mouse tumor xenograft model, in conjunction with cisplatin therapy.
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19
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Subtil FSB, Gröbner C, Recknagel N, Parplys AC, Kohl S, Arenz A, Eberle F, Dikomey E, Engenhart-Cabillic R, Schötz U. Dual PI3K/mTOR Inhibitor NVP-BEZ235 Leads to a Synergistic Enhancement of Cisplatin and Radiation in Both HPV-Negative and -Positive HNSCC Cell Lines. Cancers (Basel) 2022; 14:cancers14133160. [PMID: 35804930 PMCID: PMC9265133 DOI: 10.3390/cancers14133160] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Head and neck cancers (HNSCCs), especially in the advanced stages, are predominantly treated by radiochemotherapy, including cisplatin. The cure rates are clearly higher for HPV-positive HNSCCs when compared to HPV-negative HNSCCs. For both entities, this treatment is accompanied by serious adverse reactions, mainly due to cisplatin administration. We reported earlier that for both HPV-positive and negative HNSCC cells, the effect of radiotherapy was strongly enhanced when pretreated using the dual PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235). The current study shows that for HPV-positive cells, BEZ235 will strongly enhance the effect of cisplatin alone. More important, preincubation with BEZ235 was found to alter the purely additive effect normally seen when cisplatin is combined with radiation into a strong synergistic enhancement. This tri-modal combination might allow for the enhancement of the effect of radiochemotherapy, even with reduced cisplatin. Abstract The standard of care for advanced head and neck cancers (HNSCCs) is radiochemotherapy, including cisplatin. This treatment results in a cure rate of approximately 85% for oropharyngeal HPV-positive HNSCCs, in contrast to only 50% for HPV-negative HNSCCs, and is accompanied by severe side effects for both entities. Therefore, innovative treatment modalities are required, resulting in a better outcome for HPV-negative HNSCCs, and lowering the adverse effects for both entities. The effect of the dual PI3K/mTOR inhibitor NVP-BEZ235 on a combined treatment with cisplatin and radiation was studied in six HPV-negative and six HPV-positive HNSCC cell lines. Cisplatin alone was slightly more effective in HPV-positive cells. This could be attributed to a defect in homologous recombination, as demonstrated by depleting RAD51. Solely for HPV-positive cells, pretreatment with BEZ235 resulted in enhanced cisplatin sensitivity. For the combination of cisplatin and radiation, additive effects were observed. However, when pretreated with BEZ235, this combination changed into a synergistic interaction, with a slightly stronger enhancement for HPV-positive cells. This increase could be attributed to a diminished degree of DSB repair in G1, as visualized via the detection of γH2AX/53BP1 foci. BEZ235 can be used to enhance the effect of combined treatment with cisplatin and radiation in both HPV-negative and -positive HNSCCs.
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Affiliation(s)
- Florentine S. B. Subtil
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Carolin Gröbner
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Niklas Recknagel
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Ann Christin Parplys
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Sibylla Kohl
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Andrea Arenz
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Fabian Eberle
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Ekkehard Dikomey
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Rita Engenhart-Cabillic
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
| | - Ulrike Schötz
- Department of Radiotherapy and Radiooncology, Philipps-University, 35043 Marburg, Germany; (F.S.B.S.); (C.G.); (N.R.); (A.C.P.); (S.K.); (A.A.); (F.E.); (E.D.); (R.E.-C.)
- Correspondence: ; Tel.: +49-6421-28-21978
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Xu C, Minaguchi T, Qi N, Fujieda K, Suto A, Itagaki H, Shikama A, Tasaka N, Akiyama A, Nakao S, Ochi H, Satoh T. Differential roles of the Wip1-p38-p53 DNA damage response pathway in early/advanced-stage ovarian clear cell carcinomas. World J Surg Oncol 2022; 20:139. [PMID: 35490254 PMCID: PMC9055709 DOI: 10.1186/s12957-022-02600-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 04/16/2022] [Indexed: 11/10/2022] Open
Abstract
Background Ovarian clear cell carcinoma (OCCC) is one of the most lethal types of ovarian cancer. Early-stage OCCC can be cured by surgery; however, advanced-stage disease shows poor prognosis due to chemoresistance unlike the more common high-grade serous carcinoma. Methods We explored the differential roles of the Wip1–p38–p53 DNA damage response pathway in respective early- or advanced-stage OCCC by immunohistochemistry of Wip1, phospho-p38, p53, and phospho-p53 from consecutive 143 patients. Results High Wip1 expression correlated with positive p53 (p=0.011), which in turn correlated with low nuclear phospho-p38 expression (p=0.0094). In the early stages, positive p53 showed trends toward worse overall survival (OS) (p=0.062), whereas in the advanced stages, high Wip1 correlated with worse OS (p=0.0012). The univariate and multivariate analyses of prognostic factors indicated that high Wip1 was significant and independent for worse OS (p=0.011) in the advanced stages, but not in the early stages. Additionally, high Wip1 showed trends toward shorter treatment-free interval (TFI) in the advanced stages, but not in the early stages (p=0.083 vs. 0.93). Furthermore, high Wip1 was significantly associated with positive p53 only in the patients with shorter TFI (<6 months), but not in those with longer TFI (≥6 months) (p=0.036 vs. 0.34). Conclusions Wip1 appears to play a crucial role for the prognosis of OCCC through chemoresistance specifically in the advanced stages, implicating that Wip1 possibly serves as a reasonable therapeutic target for improving chemoresistance and poor prognosis of advanced-stage OCCC.
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Affiliation(s)
- Chenyang Xu
- Doctoral Program in Obstetrics and Gynecology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8577, Japan
| | - Takeo Minaguchi
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8575, Japan.
| | - Nan Qi
- Doctoral Program in Obstetrics and Gynecology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8577, Japan
| | - Kaoru Fujieda
- Doctoral Program in Obstetrics and Gynecology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8577, Japan
| | - Asami Suto
- Doctoral Program in Obstetrics and Gynecology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8577, Japan
| | - Hiroya Itagaki
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8575, Japan
| | - Ayumi Shikama
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8575, Japan
| | - Nobutaka Tasaka
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8575, Japan
| | - Azusa Akiyama
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8575, Japan
| | - Sari Nakao
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8575, Japan
| | - Hiroyuki Ochi
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8575, Japan
| | - Toyomi Satoh
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tsukuba, Ibaraki, 305-8575, Japan
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Lai HT, Canoy RJ, Campanella M, Vassetzky Y, Brenner C. Ca2+ Transportome and the Interorganelle Communication in Hepatocellular Carcinoma. Cells 2022; 11:cells11050815. [PMID: 35269437 PMCID: PMC8909868 DOI: 10.3390/cells11050815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/22/2022] [Accepted: 02/24/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of liver cancer with a poor prognosis for survival given the complications it bears on the patient. Though damages to the liver are acknowledged prodromic factors, the precise molecular aetiology remains ill-defined. However, many genes coding for proteins involved in calcium (Ca2+) homeostasis emerge as either mutated or deregulated. Ca2+ is a versatile signalling messenger that regulates functions that prime and drive oncogenesis, favouring metabolic reprogramming and gene expression. Ca2+ is present in cell compartments, between which it is trafficked through a network of transporters and exchangers, known as the Ca2+ transportome. The latter regulates and controls Ca2+ dynamics and tonicity. In HCC, the deregulation of the Ca2+ transportome contributes to tumorigenesis, the formation of metastasizing cells, and evasion of cell death. In this review, we reflect on these aspects by summarizing the current knowledge of the Ca2+ transportome and overviewing its composition in the plasma membrane, endoplasmic reticulum, and the mitochondria.
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Affiliation(s)
- Hong-Toan Lai
- CNRS, Institut Gustave Roussy, Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France; (H.-T.L.); (R.J.C.); (M.C.); (Y.V.)
| | - Reynand Jay Canoy
- CNRS, Institut Gustave Roussy, Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France; (H.-T.L.); (R.J.C.); (M.C.); (Y.V.)
- Institute of Human Genetics, National Institutes of Health, University of the Philippines, Manila 1000, Philippines
| | - Michelangelo Campanella
- CNRS, Institut Gustave Roussy, Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France; (H.-T.L.); (R.J.C.); (M.C.); (Y.V.)
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London NW1 0TU, UK
- Consortium for Mitochondrial Research, University College London, London WC1 0TU, UK
- Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Yegor Vassetzky
- CNRS, Institut Gustave Roussy, Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France; (H.-T.L.); (R.J.C.); (M.C.); (Y.V.)
| | - Catherine Brenner
- CNRS, Institut Gustave Roussy, Aspects Métaboliques et Systémiques de l’Oncogénèse pour de Nouvelles Approches Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France; (H.-T.L.); (R.J.C.); (M.C.); (Y.V.)
- Correspondence:
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Wang F, Gouttia OG, Wang L, Peng A. PARP1 Upregulation in Recurrent Oral Cancer and Treatment Resistance. Front Cell Dev Biol 2022; 9:804962. [PMID: 35071239 PMCID: PMC8769238 DOI: 10.3389/fcell.2021.804962] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/10/2021] [Indexed: 12/12/2022] Open
Abstract
First-line treatments for oral cancer typically include surgery, radiation, and in some cases, chemotherapy. Radiation and oral cancer chemotherapeutics confer cytotoxicity largely by inducing DNA damage, underscoring the importance of the cellular DNA damage repair and response pathways in cancer therapy. However, tumor recurrence and acquired resistance, following the initial response to treatment, remains as a major clinical challenge. By analyzing oral tumor cells derived from the primary and recurrent tumors of the same patient, our study revealed upregulated PARP1 expression in the recurrent tumor cells. Cisplatin and 5-fluorouracil treatment further augmented PARP1 expression in the recurrent, but not the primary, tumor cells. Post-treatment upregulation of PARP1 was dependent on the catalytic activities of PARP and CDK7. Consistent with the established function of PARP1 in DNA repair, we showed that overexpression of PARP1 rendered the primary tumor cells highly resistant to DNA damage treatment. Conversely, PARP inhibition partially reversed the treatment resistance in the recurrent tumor cells; combinatorial treatment using a PARP inhibitor and cisplatin/5-fluorouracil significantly sensitized the tumor response in vivo. Taken together, we reported here PARP1 upregulation as a clinically relevant mechanism involved in oral cancer recurrence, and suggested the clinical benefit of PARP inhibitors, currently approved for the treatment of several other types of cancer, in oral cancer.
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Affiliation(s)
- Feifei Wang
- Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, United States
| | - Odjo G Gouttia
- Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, United States
| | - Ling Wang
- Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, United States
| | - Aimin Peng
- Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, United States
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Stucci LS, Internò V, Tucci M, Perrone M, Mannavola F, Palmirotta R, Porta C. The ATM Gene in Breast Cancer: Its Relevance in Clinical Practice. Genes (Basel) 2021; 12:727. [PMID: 34068084 PMCID: PMC8152746 DOI: 10.3390/genes12050727] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/09/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022] Open
Abstract
Molecular alterations of the Ataxia-telangiectasia (AT) gene are frequently detected in breast cancer (BC), with an incidence ranging up to 40%. The mutated form, the Ataxia-telangiectasia mutated (ATM) gene, is involved in cell cycle control, apoptosis, oxidative stress, and telomere maintenance, and its role as a risk factor for cancer development is well established. Recent studies have confirmed that some variants of ATM are associated with an increased risk of BC development and a worse prognosis. Thus, many patients harboring ATM mutations develop intermediate- and high-grade disease, and there is a higher rate of lymph node metastatic involvement. The evidence concerning a correlation of ATM gene mutations and the efficacy of therapeutic strategies in BC management are controversial. In fact, ATM mutations may sensitize cancer cells to platinum-derived drugs, as BRCA1/2 mutations do, whereas their implications in objective responses to hormonal therapy or target-based agents are not well defined. Herein, we conducted a review of the role of ATM gene mutations in BC development, prognosis, and different treatment strategies.
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Affiliation(s)
- Luigia Stefania Stucci
- Division of Medical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, A.O.U. Consorziale Policlinico di Bari, 70121 Bari, Italy; (V.I.); (M.T.); (M.P.); (F.M.); (C.P.)
| | - Valeria Internò
- Division of Medical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, A.O.U. Consorziale Policlinico di Bari, 70121 Bari, Italy; (V.I.); (M.T.); (M.P.); (F.M.); (C.P.)
| | - Marco Tucci
- Division of Medical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, A.O.U. Consorziale Policlinico di Bari, 70121 Bari, Italy; (V.I.); (M.T.); (M.P.); (F.M.); (C.P.)
- National Cancer Research Center, Tumori Institute IRCCS Giovanni Paolo II, 70121 Bari, Italy
| | - Martina Perrone
- Division of Medical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, A.O.U. Consorziale Policlinico di Bari, 70121 Bari, Italy; (V.I.); (M.T.); (M.P.); (F.M.); (C.P.)
| | - Francesco Mannavola
- Division of Medical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, A.O.U. Consorziale Policlinico di Bari, 70121 Bari, Italy; (V.I.); (M.T.); (M.P.); (F.M.); (C.P.)
| | - Raffaele Palmirotta
- Interdisciplinary Department of Medicine, Section of Sciences and Technologies of Laboratory Medicine, University of Bari, 70121 Bari, Italy;
| | - Camillo Porta
- Division of Medical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, A.O.U. Consorziale Policlinico di Bari, 70121 Bari, Italy; (V.I.); (M.T.); (M.P.); (F.M.); (C.P.)
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de Almeida LC, Calil FA, Machado-Neto JA, Costa-Lotufo LV. DNA damaging agents and DNA repair: From carcinogenesis to cancer therapy. Cancer Genet 2021; 252-253:6-24. [DOI: 10.1016/j.cancergen.2020.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/30/2020] [Accepted: 12/02/2020] [Indexed: 02/09/2023]
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Vaidya FU, Sufiyan Chhipa A, Mishra V, Gupta VK, Rawat SG, Kumar A, Pathak C. Molecular and cellular paradigms of multidrug resistance in cancer. Cancer Rep (Hoboken) 2020; 5:e1291. [PMID: 33052041 PMCID: PMC9780431 DOI: 10.1002/cnr2.1291] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND The acquisition of resistance to chemotherapy is a major hurdle in the successful application of cancer therapy. Several anticancer approaches, including chemotherapies, radiotherapy, surgery and targeted therapies are being employed for the treatment of cancer. However, cancer cells reprogram themselves in multiple ways to evade the effect of these therapies, and over a period of time, the drug becomes inactive due to the development of multi-drug resistance (MDR). MDR is a complex phenomenon where malignant cells become insensitive to anticancer drugs and attain the ability to survive even after several exposures of anticancer drugs. In this review, we have discussed the molecular and cellular paradigms of multidrug resistance in cancer. RECENT FINDINGS An Extensive research in cancer biology revealed that drug resistance in cancer is the result of perpetuated intracellular and extracellular mechanisms such as drug efflux, drug inactivation, drug target alteration, oncogenic mutations, altered DNA damage repair mechanism, inhibition of programmed cell death signaling, metabolic reprogramming, epithelial mesenchymal transition (EMT), inherent cell heterogeneity, epigenetic changes, redox imbalance, or any combination of these mechanisms. An inevitable cross-link between inflammation and drug resistance has been discussed. This review provided insight molecular mechanism to understand the vulnerabilities of cancer cells to develop drug resistance. CONCLUSION MDR is an outcome of interplays between multiple intricate pathways responsible for the inactivation of drug and development of resistance. MDR is a major obstacle in regimens of successful application of anti-cancer therapy. An improved understanding of the molecular mechanism of multi drug resistance and cellular reprogramming can provide a promising opportunity to combat drug resistance in cancer and intensify anti-cancer therapy for the upcoming future.
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Affiliation(s)
- Foram U. Vaidya
- Cell Biology Laboratory, School of Biological Sciences & BiotechnologyIndian Institute of Advanced ResearchGandhinagarIndia
| | - Abu Sufiyan Chhipa
- Cell Biology Laboratory, School of Biological Sciences & BiotechnologyIndian Institute of Advanced ResearchGandhinagarIndia
| | - Vinita Mishra
- Cell Biology Laboratory, School of Biological Sciences & BiotechnologyIndian Institute of Advanced ResearchGandhinagarIndia
| | | | | | - Ajay Kumar
- Department of ZoologyBanaras Hindu UniversityVaranasiIndia
| | - Chandramani Pathak
- Cell Biology Laboratory, School of Biological Sciences & BiotechnologyIndian Institute of Advanced ResearchGandhinagarIndia
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Broccoli extract increases drug-mediated cytotoxicity towards cancer stem cells of head and neck squamous cell carcinoma. Br J Cancer 2020; 123:1395-1403. [PMID: 32773768 PMCID: PMC7591858 DOI: 10.1038/s41416-020-1025-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 07/01/2020] [Accepted: 07/23/2020] [Indexed: 02/06/2023] Open
Abstract
Background Head and neck squamous cell carcinomas (HNSCC) are malignant neoplasms with poor prognosis. Treatment-resistant cancer stem cell (CSC) is one reason for treatment failure. Considerable attention has been focused on sulforaphane (SF), a phytochemical from broccoli possessing anticancer properties. We investigated whether SF could enhance the chemotherapeutic effects of cisplatin (CIS) and 5-fluorouracil (5-FU) against HNSCC–CSCs, and its mechanisms of action. Methods CD44+/CD271+ FACS-isolated CSCs from SCC12 and SCC38 human cell lines were treated with SF alone or combined with CIS or 5-FU. Cell viability, colony- and sphere-forming ability, apoptosis, CSC-related gene and protein expression and in vivo tumour growth were assessed. Safety of SF was tested on non-cancerous stem cells and in vivo. Results SF reduced HNSCC–CSC viability in a time- and dose-dependent manner. Combining SF increased the cytotoxicity of CIS twofold and 5-FU tenfold, with no effects on non-cancerous stem cell viability and functions. SF-combined treatments inhibited CSC colony and sphere formation, and tumour progression in vivo. Potential mechanisms of action included the stimulation of caspase-dependent apoptotic pathway, inhibition of SHH pathway and decreased expression of SOX2 and OCT4. Conclusions Combining SF allowed lower doses of CIS or 5-FU while enhancing these drug cytotoxicities against HNSCC–CSCs, with minimal effects on healthy cells.
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Deng W, Li J, Dorrah K, Jimenez-Tapia D, Arriaga B, Hao Q, Cao W, Gao Z, Vadgama J, Wu Y. The role of PPM1D in cancer and advances in studies of its inhibitors. Biomed Pharmacother 2020; 125:109956. [PMID: 32006900 PMCID: PMC7080581 DOI: 10.1016/j.biopha.2020.109956] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/08/2020] [Accepted: 01/23/2020] [Indexed: 12/16/2022] Open
Abstract
A greater understanding of factors causing cancer initiation, progression and evolution is of paramount importance. Among them, the serine/threonine phosphatase PPM1D, also referred to as wild-type p53-induced phosphatase 1 (Wip1) or protein phosphatase 2C delta (PP2Cδ), is emerging as an important oncoprotein due to its negative regulation on a number of crucial cancer suppressor pathways. Initially identified as a p53-regulated gene, PPM1D has been afterwards found amplified and more recently mutated in many human cancers such as breast cancer. The latest progress in this field further reveals that selective inhibition of PPM1D to delay tumor onset or reduce tumor burden represents a promising anti-cancer strategy. Here, we review the advances in the studies of the PPM1D activity and its relevance to various cancers, and recent progress in development of PPM1D inhibitors and discuss their potential application in cancer therapy. Consecutive research on PPM1D and its relationship with cancer is essential, as it ultimately contributes to the etiology and treatment of cancer.
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Affiliation(s)
- Wenhong Deng
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China; Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Jieqing Li
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Kimberly Dorrah
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Denise Jimenez-Tapia
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Brando Arriaga
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Qiongyu Hao
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Wei Cao
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Zhaoxia Gao
- Department of General Surgery, 5th Hospital of Wuhan, Wuhan, 430050, China; Department of Surgery, Johns Hopkins Hospital Bayview Campus, Baltimore, MD, USA
| | - Jay Vadgama
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
| | - Yong Wu
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
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Lin S, Chang C, Hsu C, Tsai M, Cheng H, Leong MK, Sung P, Chen J, Weng C. Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence. Br J Pharmacol 2020; 177:1409-1423. [PMID: 31368509 PMCID: PMC7056458 DOI: 10.1111/bph.14816] [Citation(s) in RCA: 239] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 07/19/2019] [Accepted: 07/26/2019] [Indexed: 12/11/2022] Open
Abstract
Traditional chemotherapy is being considered due to hindrances caused by systemic toxicity. Currently, the administration of multiple chemotherapeutic drugs with different biochemical/molecular targets, known as combination chemotherapy, has attained numerous benefits like efficacy enhancement and amelioration of adverse effects that has been broadly applied to various cancer types. Additionally, seeking natural-based alternatives with less toxicity has become more important. Experimental evidence suggests that herbal extracts such as Solanum nigrum and Claviceps purpurea and isolated herbal compounds (e.g., curcumin, resveratrol, and matairesinol) combined with antitumoral drugs have the potential to attenuate resistance against cancer therapy and to exert chemoprotective actions. Plant products are not free of risks: Herb adverse effects, including herb-drug interactions, should be carefully considered. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.
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Affiliation(s)
- Shian‐Ren Lin
- Department of Life Science and Institute of BiotechnologyNational Dong Hwa UniversityHualienTaiwan
| | - Chia‐Hsiang Chang
- Department of Life Science and Institute of BiotechnologyNational Dong Hwa UniversityHualienTaiwan
| | - Che‐Fang Hsu
- Department of Life Science and Institute of BiotechnologyNational Dong Hwa UniversityHualienTaiwan
- Center for Prevention and Therapy of Gynaecological Cancers, Department of ResearchTzu Chi HospitalHualienTaiwan
| | - May‐Jwan Tsai
- Neural Regeneration Laboratory, Neurological InstituteTaipei Veterans General HospitalTaipei CityTaiwan
| | - Henrich Cheng
- Neural Regeneration Laboratory, Neurological InstituteTaipei Veterans General HospitalTaipei CityTaiwan
| | - Max K. Leong
- Department of ChemistryNational Dong Hwa UniversityHualienTaiwan
| | - Ping‐Jyun Sung
- Graduate Institute of Marine BiotechnologyNational Dong Hwa UniversityPingtungTaiwan
| | - Jian‐Chyi Chen
- Department of BiotechnologySouthern Taiwan University of Science and TechnologyTainan CityTaiwan
| | - Ching‐Feng Weng
- Graduate Institute of Marine BiotechnologyNational Dong Hwa UniversityPingtungTaiwan
- Department of Basic Medical Science, Center for Transitional MedicineXiamen Medical CollegeXiamenChina
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29
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Zhu S, Paydar M, Wang F, Li Y, Wang L, Barrette B, Bessho T, Kwok BH, Peng A. Kinesin Kif2C in regulation of DNA double strand break dynamics and repair. eLife 2020; 9:53402. [PMID: 31951198 PMCID: PMC7012618 DOI: 10.7554/elife.53402] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 01/16/2020] [Indexed: 12/12/2022] Open
Abstract
DNA double strand breaks (DSBs) have detrimental effects on cell survival and genomic stability, and are related to cancer and other human diseases. In this study, we identified microtubule-depolymerizing kinesin Kif2C as a protein associated with DSB-mimicking DNA templates and known DSB repair proteins in Xenopus egg extracts and mammalian cells. The recruitment of Kif2C to DNA damage sites was dependent on both PARP and ATM activities. Kif2C knockdown or knockout led to accumulation of endogenous DNA damage, DNA damage hypersensitivity, and reduced DSB repair via both NHEJ and HR. Interestingly, Kif2C depletion, or inhibition of its microtubule depolymerase activity, reduced the mobility of DSBs, impaired the formation of DNA damage foci, and decreased the occurrence of foci fusion and resolution. Taken together, our study established Kif2C as a new player of the DNA damage response, and presented a new mechanism that governs DSB dynamics and repair.
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Affiliation(s)
- Songli Zhu
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Omaha, United States
| | - Mohammadjavad Paydar
- Institute for Research in Immunology and Cancer (IRIC), Département de médecine, Université de Montréal, Montréal, Canada
| | - Feifei Wang
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Omaha, United States.,Institute of Physical Science and Information Technology, Anhui University, Hefei, China
| | - Yanqiu Li
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Omaha, United States
| | - Ling Wang
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Omaha, United States
| | - Benoit Barrette
- Institute for Research in Immunology and Cancer (IRIC), Département de médecine, Université de Montréal, Montréal, Canada
| | - Tadayoshi Bessho
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, United States
| | - Benjamin H Kwok
- Institute for Research in Immunology and Cancer (IRIC), Département de médecine, Université de Montréal, Montréal, Canada
| | - Aimin Peng
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Omaha, United States
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Kakihara Y, Kiguchi T, Ohazama A, Saeki M. R2TP/PAQosome as a promising chemotherapeutic target in cancer. JAPANESE DENTAL SCIENCE REVIEW 2020; 56:38-42. [PMID: 31890057 PMCID: PMC6926247 DOI: 10.1016/j.jdsr.2019.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 07/27/2019] [Accepted: 08/21/2019] [Indexed: 11/30/2022] Open
Abstract
R2TP/PAQosome (particle for arrangement of quaternary structure) is a novel multisubunit chaperone specialized in the assembly/maturation of protein complexes that are involved in essential cellular processes such as PIKKs (phosphatidylinositol 3-kinase-like kinases) signaling, snoRNP (small nucleolar ribonucleoprotein) biogenesis, and RNAP II (RNA polymerase II) complex formation. In this review article, we describe the current understanding of R2TP/PAQosome functions and characteristics as well as how the chaperone complex is involved in oncogenesis, highlighting DNA damage response, mTOR (mammalian target of rapamycin) pathway as well as snoRNP biogenesis. Also, we discuss its possible involvement in HNSCC (head and neck squamous cell carcinoma) including OSCC (oral squamous cell carcinoma). Finally, we provide an overview of current anti-cancer drug development efforts targeting R2TP/PAQosome.
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Affiliation(s)
- Yoshito Kakihara
- Division of Dental Pharmacology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Tetsuo Kiguchi
- Division of Dental Pharmacology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Atsushi Ohazama
- Division of Oral Anatomy, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Makio Saeki
- Division of Dental Pharmacology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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31
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Wappler J, Arts M, Röth A, Heeren RMA, Peter Neumann U, Olde Damink SW, Soons Z, Cramer T. Glutamine deprivation counteracts hypoxia-induced chemoresistance. Neoplasia 2019; 22:22-32. [PMID: 31765939 PMCID: PMC6883317 DOI: 10.1016/j.neo.2019.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 10/12/2019] [Accepted: 10/14/2019] [Indexed: 12/29/2022] Open
Abstract
The microenvironment of solid tumors is a key determinant of therapy efficacy. The co-occurrence of oxygen and nutrient deprivation is a common phenomenon of the tumor microenvironment and associated with treatment resistance. Cholangiocarcinoma (CCA) is characterized by a very poor prognosis and pronounced chemoresistance. A better understanding of the underlying molecular mechanisms is urgently needed to improve therapy strategies against CCA. We sought to investigate the importance of the conditionally essential amino acid glutamine, a centrally important nutrient for a variety of solid tumors, for CCA. Glutamine levels were strongly decreased in CCA samples and the growth of established human CCA cell lines was highly dependent on glutamine. Using gradual reduction of external glutamine, we generated derivatives of CCA cell lines which were able to grow without external glutamine (termed glutamine-depleted (GD)). To analyze the effects of coincident oxygen and glutamine deprivation, GD cells were treated with cisplatin or gemcitabine under normoxia and hypoxia. Strikingly, the well-established phenomenon of hypoxia-induced chemoresistance was completely reversed in GD cells. In order to better understand the underlying mechanisms, we focused on the oncogene c-Myc. The combination of cisplatin and hypoxia led to sustained c-Myc protein expression in wildtype cells. In contrast, c-Myc expression was reduced in response to the combinatorial treatment in GD cells, suggesting a functional importance of c-Myc in the process of hypoxia-induced chemoresistance. In summary, these findings indicate that the mechanisms driving adaption to tumor microenvironmental changes and their relevance for the response to therapy are more complex than expected.
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Affiliation(s)
- Jessica Wappler
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Martijn Arts
- Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Anjali Röth
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany; ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany; ESCAM - European Surgery Center Aachen Maastricht, Maastricht, the Netherlands
| | - Ron M A Heeren
- The Maastricht MultiModal Molecular Imaging Institute (M4I), Division of Imaging Mass Spectrometry, Maastricht University, Maastricht, the Netherlands
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany; Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands; ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany; ESCAM - European Surgery Center Aachen Maastricht, Maastricht, the Netherlands
| | - Steven W Olde Damink
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany; Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands; ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany; ESCAM - European Surgery Center Aachen Maastricht, Maastricht, the Netherlands; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Zita Soons
- Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany; Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands; ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany; ESCAM - European Surgery Center Aachen Maastricht, Maastricht, the Netherlands; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
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32
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Aspirin enhances cisplatin sensitivity of resistant non-small cell lung carcinoma stem-like cells by targeting mTOR-Akt axis to repress migration. Sci Rep 2019; 9:16913. [PMID: 31729456 PMCID: PMC6858356 DOI: 10.1038/s41598-019-53134-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 10/24/2019] [Indexed: 12/20/2022] Open
Abstract
Conventional chemotherapeutic regimens are unable to prevent metastasis of non-small cell lung carcinoma (NSCLC) thereby leaving cancer incurable. Cancer stem cells (CSCs) are considered to be the origin of this therapeutic limitation. In the present study we report that the migration potential of NSCLCs is linked to its CSC content. While cisplatin alone fails to inhibit the migration of CSC-enriched NSCLC spheroids, in a combination with non-steroidal anti inflammatory drug (NSAID) aspirin retards the same. A search for the underlying mechanism revealed that aspirin pre-treatment abrogates p300 binding both at TATA-box and initiator (INR) regions of mTOR promoter of CSCs, thereby impeding RNA polymerase II binding at those sites and repressing mTOR gene transcription. As a consequence of mTOR down-regulation, Akt is deactivated via dephosphorylation at Ser473 residue thereby activating Gsk3β that in turn causes destabilization of Snail and β-catenin, thus reverting epithelial to mesenchymal transition (EMT). However, alone aspirin fails to hinder migration since it does not inhibit the Integrin/Fak pathway, which is highly activated in NSCLC stem cells. On the other hand, in aspirin pre-treated CSCs, cisplatin stalls migration by hindering the integrin pathway. These results signify the efficacy of aspirin in sensitizing NSCLC stem cells towards the anti-migration effect of cisplatin. Cumulatively, our findings raise the possibility that aspirin might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to impede migration of NSCLC stem cells otherwise. This may consequently lead to the advancement of remedial outcome for the metastatic NSCLCs.
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Morita A, Aoshima K, Gulay KCM, Onishi S, Shibata Y, Yasui H, Kobayashi A, Kimura T. High drug efflux pump capacity and low DNA damage response induce doxorubicin resistance in canine hemangiosarcoma cell lines. Res Vet Sci 2019; 127:1-10. [PMID: 31648115 DOI: 10.1016/j.rvsc.2019.09.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 09/17/2019] [Accepted: 09/22/2019] [Indexed: 01/19/2023]
Abstract
Canine hemangiosarcoma (HSA) is an aggressive malignant endothelial tumor in dogs and characterized by poor prognosis because of its high invasiveness, high metastatic potential, and poor responsiveness to anti-cancer drugs. Although doxorubicin-based chemotherapy is regularly conducted after surgical treatment, its effects on survival rates are limited. Acquisition of drug resistance is one of the causes of this problem, but the underlying mechanisms remain unclear. In the present study, we aimed to identify the drug-resistance mechanism in canine HSA by establishing doxorubicin-resistant (DR) HSA cell lines. HSA cell lines were exposed to doxorubicin at gradually increasing concentrations. When the cells were able to grow in the presence of a 16-fold higher doxorubicin concentration compared with the initial culture, they were designated DR-HSA cell lines. Characterization of these DR-HSA cell lines revealed higher drug efflux pump capacity compared with the parental cell lines. Furthermore, the DR-HSA cell lines did not show activation of the DNA damage response despite carrying high DNA damage burdens, meaning that apoptosis was not strongly induced. In conclusion, canine HSA cell lines acquired doxorubicin resistance by increasing their drug efflux pump capacity and decreasing the DNA damage response. This study provides useful findings to promote further research on the drug-resistance mechanisms in canine HSA.
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Affiliation(s)
- Atsuya Morita
- Laboratory of Comparative Pathology, Department of Clinical Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
| | - Keisuke Aoshima
- Laboratory of Comparative Pathology, Department of Clinical Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan.
| | - Kevin Christian Montecillo Gulay
- Laboratory of Comparative Pathology, Department of Clinical Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
| | - Shinichi Onishi
- Laboratory of Comparative Pathology, Department of Clinical Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
| | - Yuki Shibata
- Laboratory of Integrated Molecular Imaging, Department of Biomedical Imaging, Graduate School of Biomedical Science and Engineering, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Hironobu Yasui
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
| | - Atsushi Kobayashi
- Laboratory of Comparative Pathology, Department of Clinical Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
| | - Takashi Kimura
- Laboratory of Comparative Pathology, Department of Clinical Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
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Wang L, Sun J, Gao P, Su K, Wu H, Li J, Lou W. Wnt1-inducible signaling protein 1 regulates laryngeal squamous cell carcinoma glycolysis and chemoresistance via the YAP1/TEAD1/GLUT1 pathway. J Cell Physiol 2019; 234:15941-15950. [PMID: 30805937 DOI: 10.1002/jcp.28253] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 12/27/2018] [Accepted: 01/10/2019] [Indexed: 01/24/2023]
Abstract
Wnt1-inducible signaling protein 1 (WISP1) is a matricellular protein and downstream target of Wnt/β-catenin signaling. This study sought to determine the role of WISP1 in glucose metabolism and chemoresistance in laryngeal squamous cell carcinoma. WISP1 expression was silenced or upregulated in Hep-2 cells by the transfection of WISP1 siRNA or AdWISP1 vector. Ectopic WISP1 expression regulated glucose uptake and lactate production in Hep-2 cells. Subsequently, the expression of glucose transporter 1 (GLUT1) was significantly modulated by WISP1. Furthermore, WISP1 increased cell survival rates, diminished cell death rates, and suppressed ataxia-telangiectasia-mutated (ATM)-mediated DNA damage response pathway in cancer cells treated with cisplatin through GLUT1. WISP1 also promoted cancer cell tumorigenicity and growth in mice implanted with Hep-2 cells. Additionally, WISP1 activated the YAP1/TEAD1 pathway that consequently contributed to the regulation of GLUT1 expression. In summary, WISP1 regulated glucose metabolism and cisplatin resistance in laryngeal cancer by regulating GLUT1 expression. WISP1 may be used as a potential therapeutic target for laryngeal cancer.
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Affiliation(s)
- Liang Wang
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jin Sun
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Pei Gao
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ke Su
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huanhuan Wu
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Junli Li
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Weihua Lou
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Heijink AM, Everts M, Honeywell ME, Richards R, Kok YP, de Vries EGE, Lee MJ, van Vugt MATM. Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity. Cell Rep 2019; 28:2345-2357.e5. [PMID: 31461651 PMCID: PMC6718811 DOI: 10.1016/j.celrep.2019.07.070] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 05/24/2019] [Accepted: 07/22/2019] [Indexed: 12/31/2022] Open
Abstract
Triple-negative breast cancers (TNBCs) display great diversity in cisplatin sensitivity that cannot be explained solely by cancer-associated DNA repair defects. Differential activation of the DNA damage response (DDR) to cisplatin has been proposed to underlie the observed differential sensitivity, but it has not been investigated systematically. Systems-level analysis-using quantitative time-resolved signaling data and phenotypic responses, in combination with mathematical modeling-identifies that the activation status of cell-cycle checkpoints determines cisplatin sensitivity in TNBC cell lines. Specifically, inactivation of the cell-cycle checkpoint regulator MK2 or G3BP2 sensitizes cisplatin-resistant TNBC cell lines to cisplatin. Dynamic signaling data of five cell cycle-related signals predicts cisplatin sensitivity of TNBC cell lines. We provide a time-resolved map of cisplatin-induced signaling that uncovers determinants of chemo-sensitivity, underscores the impact of cell-cycle checkpoints on cisplatin sensitivity, and offers starting points to optimize treatment efficacy.
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Affiliation(s)
- Anne Margriet Heijink
- Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
| | - Marieke Everts
- Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
| | - Megan E Honeywell
- Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Ryan Richards
- Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Yannick P Kok
- Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
| | - Elisabeth G E de Vries
- Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
| | - Michael J Lee
- Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
| | - Marcel A T M van Vugt
- Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands.
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36
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Yuan Y, Cai T, Callaghan R, Li Q, Huang Y, Wang B, Huang Q, Du M, Ma Q, Chiba P, Cai Y. Psoralen-loaded lipid-polymer hybrid nanoparticles enhance doxorubicin efficacy in multidrug-resistant HepG2 cells. Int J Nanomedicine 2019; 14:2207-2218. [PMID: 30988617 PMCID: PMC6443224 DOI: 10.2147/ijn.s189924] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background Psoralen (PSO), a major active component of Psoralea corylifolia, has been shown to overcome multidrug resistance in cancer. A drug carrier comprising a lipid-monolayer shell and a biodegradable polymer core for sustained delivery and improved efficacy of drug have exhibited great potential in efficient treatment of cancers. Methods The PSO-loaded lipid polymer hybrid nanoparticles were prepared and characterized. In vitro cytotoxicity assay, cellular uptake, cell cycle analysis, detection of ROS level and mitochondrial membrane potential (ΔΨm) and western blot were performed. Results The P-LPNs enhanced the cytotoxicity of doxorubicin (DOX) 17-fold compared to free DOX in multidrug resistant HepG2/ADR cells. Moreover, P-LPNs displayed pro-apoptotic activity, increased levels of ROS and depolarization of ΔΨm. In addition, there were no signifi-cant effects on cellular uptake of DOX, cell cycle arrest, or the expression of P-glycoprotein. Mechanistic studies suggested that P-LPNs enhanced DOX cytotoxicity by increased release of cytochrome c and enhanced caspase3 cleavage, causing apoptosis in HepG2/ADR cells. Conclusion The lipid-polymer hybrid nanoparticles can be considered a powerful and promising drug delivery system for effective cancer chemotherapy.
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Affiliation(s)
- Yueling Yuan
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China,
| | - Tiange Cai
- College of Life Science, Liaoning University, Shenyang, Liaoning 110000, China
| | - Richard Callaghan
- Research School of Biology, Australian National University, Canberra ACT 2601, Australia
| | - Qianwen Li
- Guangzhou Guoyu Pharmaceutical Technology Co., Ltd., Guangzhou, Guangdong 510663, China
| | - Yinghong Huang
- Guangzhou Guoyu Pharmaceutical Technology Co., Ltd., Guangzhou, Guangdong 510663, China
| | - Bingyue Wang
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China,
| | - Qingqing Huang
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China,
| | - Manling Du
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China,
| | - Qianqian Ma
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China,
| | - Peter Chiba
- Institute of Medical Chemistry, Medical University of Vienna, Vienna 1090, Austria,
| | - Yu Cai
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China, .,Cancer Research Institute, Jinan University, Guangzhou, Guangdong 510632, China,
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37
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Wang F, Zhu S, Fisher LA, Wang L, Eurek NJ, Wahl JK, Lan L, Peng A. Phosphatase 1 Nuclear Targeting Subunit Mediates Recruitment and Function of Poly (ADP-Ribose) Polymerase 1 in DNA Repair. Cancer Res 2019; 79:2526-2535. [PMID: 30733193 DOI: 10.1158/0008-5472.can-18-1673] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 10/26/2018] [Accepted: 01/31/2019] [Indexed: 12/17/2022]
Abstract
PARP, particularly PARP1, plays an essential role in the detection and repair of DNA single-strand breaks and double-strand breaks. PARP1 accumulates at DNA damage sites within seconds after DNA damage to catalyze the massive induction of substrate protein poly ADP-ribosylation (PARylation). However, the molecular mechanisms underlying the recruitment and activation of PARP1 in DNA repair are not fully understood. Here we show that phosphatase 1 nuclear targeting subunit 1 (PNUTS) is a robust binding partner of PARP1. Inhibition of PNUTS led to strong accumulation of endogenous DNA damage and sensitized the cellular response to a wide range of DNA-damaging agents, implicating PNUTS as an essential and multifaceted regulator of DNA repair. Recruitment of PNUTS to laser-induced DNA damage was similar to that of PARP1, and depletion or inhibition of PARP1 abrogated recruitment of PNUTS to sites of DNA damage. Conversely, PNUTS was required for efficient induction of substrate PARylation after DNA damage. PNUTS bound the BRCA1 C-terminal (BRCT) domain of PARP1 and was required for the recruitment of PARP1 to sites of DNA damage. Finally, depletion of PNUTS rendered cancer cells hypersensitive to PARP inhibition. Taken together, our study characterizes PNUTS as an essential partner of PARP1 in DNA repair and a potential drug target in cancer therapy. SIGNIFICANCE: These findings reveal PNUTS as an essential functional partner of PARP1 in DNA repair and suggest its inhibition as a potential therapeutic strategy in conjunction with DNA-damaging agents or PARP inhibitors.See related commentary by Murai and Pommier, p. 2460.
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Affiliation(s)
- Feifei Wang
- Institute of Physical Science and Information Technology, Anhui University, Hefei, P.R. China.,Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, Nebraska
| | - Songli Zhu
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, Nebraska
| | - Laura A Fisher
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, Nebraska
| | - Ling Wang
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, Nebraska
| | - Nicholas J Eurek
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, Nebraska
| | - James K Wahl
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, Nebraska
| | - Li Lan
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Aimin Peng
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, Nebraska.
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Merlos Rodrigo MA, Buchtelova H, de Los Rios V, Casal JI, Eckschlager T, Hrabeta J, Belhajova M, Heger Z, Adam V. Proteomic Signature of Neuroblastoma Cells UKF-NB-4 Reveals Key Role of Lysosomal Sequestration and the Proteasome Complex in Acquiring Chemoresistance to Cisplatin. J Proteome Res 2019; 18:1255-1263. [PMID: 30592607 DOI: 10.1021/acs.jproteome.8b00867] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cisplatin (CDDP) is a widely used agent in the treatment of neuroblastoma. Unfortunately, the development of acquired chemoresistance limits its clinical use. To gain a detailed understanding of the mechanisms underlying the development of such chemoresistance, we comparatively analyzed established cisplatin-resistant neuroblastoma cell line (UKF-NB-4CDDP) and its sensitive counterpart (UKF-NB-4). First, using viability screenings, we confirmed the decreased sensitivity of tested cells to cisplatin and identified a cross-resistance to carboplatin and oxaliplatin. Then, the proteomic signatures were analyzed using nano liquid chromatography with tandem mass spectrometry. Among the proteins responsible for UKF-NB-4CDDP chemoresistance, ion channels transport family proteins, ATP-binding cassette superfamily proteins (ATP = adenosine triphosphate), solute carrier-mediated trans-membrane transporters, proteasome complex subunits, and V-ATPases were identified. Moreover, we detected markedly higher proteasome activity in UKF-NB-4CDDP cells and a remarkable lysosomal enrichment that can be inhibited by bafilomycin A to sensitize UKF-NB-4CDDP to CDDP. Our results indicate that lysosomal sequestration and proteasome activity may be one of the key mechanisms responsible for intrinsic chemoresistance of neuroblastoma to CDDP.
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Affiliation(s)
- Miguel Angel Merlos Rodrigo
- Department of Chemistry and Biochemistry , Mendel University in Brno , Zemedelska 1 , 613 00 Brno , Czech Republic.,Central European Institute of Technology , Brno University of Technology , Purkynova 123 , 612 00 Brno , Czech Republic
| | - Hana Buchtelova
- Department of Chemistry and Biochemistry , Mendel University in Brno , Zemedelska 1 , 613 00 Brno , Czech Republic.,Central European Institute of Technology , Brno University of Technology , Purkynova 123 , 612 00 Brno , Czech Republic
| | - Vivian de Los Rios
- Functional Proteomics, Department of Molecular Biomedicine and Proteomic Facility , Centro de Investigaciones Biológicas , Ramiro de Maeztu 9 , Madrid 280 40 , Spain
| | - José Ignacio Casal
- Functional Proteomics, Department of Molecular Biomedicine and Proteomic Facility , Centro de Investigaciones Biológicas , Ramiro de Maeztu 9 , Madrid 280 40 , Spain
| | - Tomas Eckschlager
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine , Charles University, and University Hospital Motol , V Uvalu 84 , 150 06 Prague 5 , Czech Republic
| | - Jan Hrabeta
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine , Charles University, and University Hospital Motol , V Uvalu 84 , 150 06 Prague 5 , Czech Republic
| | - Marie Belhajova
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine , Charles University, and University Hospital Motol , V Uvalu 84 , 150 06 Prague 5 , Czech Republic
| | - Zbynek Heger
- Department of Chemistry and Biochemistry , Mendel University in Brno , Zemedelska 1 , 613 00 Brno , Czech Republic.,Central European Institute of Technology , Brno University of Technology , Purkynova 123 , 612 00 Brno , Czech Republic
| | - Vojtech Adam
- Department of Chemistry and Biochemistry , Mendel University in Brno , Zemedelska 1 , 613 00 Brno , Czech Republic.,Central European Institute of Technology , Brno University of Technology , Purkynova 123 , 612 00 Brno , Czech Republic
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Zhang B, Cui B, Du J, Shen X, Wang K, Chen J, Xiao L, Sun C, Li Y. ATR activated by EB virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma. Cancer Manag Res 2019; 11:573-585. [PMID: 30666155 PMCID: PMC6331066 DOI: 10.2147/cmar.s187099] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Purpose Epstein-Barr virus (EBV) infection is closely associated with nasopharyngeal carcinoma (NPC) and increases the chemotherapy resistance of tumor cells. Although the mechanism by which EBV manipulates ataxia telangiectasia mutation (ATM)-mediated DNA damage response in NPC has been extensively studied, the relationship between ATR (ATM and Rad-3 related) and EBV infection is largely unexplored, and also the role of ATR in chemotherapy resistance in EBV-positive NPC has not been specifically reported. Materials and methods Levels of γ-H2AX, latent membrane protein 1 (LMP1), and EBV-encoded RNA in clinical NPC and nasopharyngeal inflammation (NPI) specimens were examined using immunohistochemistry and in situ hybridization. The effects of EBV infection, chemotherapy drugs cisplatin (CDDP) and 5-fluorouracil (5-FU) treatment, and ATR silencing were assessed in NPC cells in vitro using immunofluorescence, Western blot, and flow cytometry. Results A notable increase of γ-H2AX expression was examined in the EBV-positive NPC clinical specimens. Additionally, we observed that the phosphorylation of ATR/checkpoint kinase 1 (CHK1) pathway protein was gradually activated along with the duration of EBV exposure in NPC cell lines, which was obviously inhibited after ATR depletion. Moreover, EBV infection promoted the resistance of NPC cells to CDDP and 5-FU, whereas the chemosensitivity of cells was significantly enhanced following ATR knockdown. Furthermore, ATR depletion caused both S-phase cell arrest and apoptosis, enhanced p53 phosphorylation, and impaired the formation of Rad51. Conclusion Our data suggest that EBV activation of ATR-mediated DNA damage response might result in chemotherapy resistance to CDDP and 5-FU in NPC. Accordingly, ATR knockdown may serve as an effective treatment strategy for chemotherapy-resistant, EBV-positive NPC.
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Affiliation(s)
- Bo Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, ;
| | - Bomiao Cui
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, ;
| | - Jintao Du
- Department of Otorhinolaryngology-Head and Neck Surgery, West China Hospital, Chengdu 610041, Sichuan, China
| | - Xin Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, ;
| | - Kun Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, ;
| | - Jiao Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, ;
| | - Liying Xiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, ;
| | - Chongkui Sun
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, ;
| | - Yan Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China, ;
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Sun J, Xu Z, Lv H, Wang Y, Wang L, Ni Y, Wang X, Hu C, Chen S, Teng F, Chen W, Cheng X. eIF5A2 regulates the resistance of gastric cancer cells to cisplatin via induction of EMT. Am J Transl Res 2018; 10:4269-4279. [PMID: 30662669 PMCID: PMC6325524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 11/16/2018] [Indexed: 06/09/2023]
Abstract
Cisplatin is the first-line chemotherapy drug for gastric cancer (GC), but treatment failure often occurs due to development of resistance. The mechanism of cisplatin resistance remains a mystery. Eukaryotic translation initiation factor 5A2 (eIF5A2) is an important tumor-promoting factor and has been rarely studied in GC. This study aimed to investigate the role of eIF5A2 in cisplatin resistance of GC cells and its relationship with epithelial-mesenchymal transition (EMT). We found that it is negative correlation between cisplatin resistance and eIF5A2's expression in GC cells. Silencing of eIF5A2 enhanced the sensitivity of GC cells to cisplatin, while overexpression of eIF5A2 decreased sensitivity. Cisplatin treatment induced gene expression changes consistent with EMT. EMT was blocked and the sensitivity of GC cells to cisplatin was increased by inhibiting the expression of Twist, indicating that EMT regulates the sensitivity of GC cells to cisplatin. Knockdown of eIF5A2 was associated with upregulation of the epithelial markers E-cadherin and β-catenin, while the expression of mesenchymal markers vimentin and N-cadherin decreased, indicating that eIF5A2 can reverse the EMT process and block the effect of cisplatin on EMT-related markers. Knockdown or overexpression of eIF5A2 did not affect the sensitivity of gastric cancer cells to cisplatin by Twist siRNA. Altogether, these data suggest that eIF5A2 regulates the resistance of gastric cancer cells to cisplatin by mediating EMT, and support the conclusion that eIF5A2 may be a molecular target for anti-tumor therapy.
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Affiliation(s)
- Jiancheng Sun
- First Clinical Medical College, Zhejiang Chinese Medical UniversityHangzhou 310053, Zhejiang, P.R. China
| | - Zhiyuan Xu
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diagnosis and Treatment of Digestive System TumorHangzhou, Zhejiang, P.R. China
- Department of Gastrointestinal Surgery, Zhejiang Hospital of Traditional Chinese Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou 310006, Zhejiang, P.R. China
| | - Hang Lv
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diagnosis and Treatment of Digestive System TumorHangzhou, Zhejiang, P.R. China
| | - Yiping Wang
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diagnosis and Treatment of Digestive System TumorHangzhou, Zhejiang, P.R. China
| | - Lijing Wang
- Department of Medical Imaging, Zhejiang Provincial Tumor HospitalHangzhou 310022, Zhejiang, P.R. China
| | - Yixiu Ni
- First Clinical Medical College, Zhejiang Chinese Medical UniversityHangzhou 310053, Zhejiang, P.R. China
| | - Xiaofeng Wang
- First Clinical Medical College, Zhejiang Chinese Medical UniversityHangzhou 310053, Zhejiang, P.R. China
| | - Can Hu
- First Clinical Medical College, Zhejiang Chinese Medical UniversityHangzhou 310053, Zhejiang, P.R. China
| | - Shangqi Chen
- First Clinical Medical College, Zhejiang Chinese Medical UniversityHangzhou 310053, Zhejiang, P.R. China
| | - Fei Teng
- First Clinical Medical College, Zhejiang Chinese Medical UniversityHangzhou 310053, Zhejiang, P.R. China
| | - Wei Chen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese MedicineHangzhou 310012, Zhejiang, P.R. China
| | - Xiangdong Cheng
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diagnosis and Treatment of Digestive System TumorHangzhou, Zhejiang, P.R. China
- Department of Abdominal Surgery, Zhejiang Cancer Hospital1# Banshan Road, Hangzhou 310022, Zhejiang, P.R. China
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Elkashty OA, Ashry R, Elghanam GA, Pham HM, Su X, Stegen C, Tran SD. Broccoli extract improves chemotherapeutic drug efficacy against head-neck squamous cell carcinomas. Med Oncol 2018; 35:124. [PMID: 30078069 DOI: 10.1007/s12032-018-1186-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 07/31/2018] [Indexed: 12/17/2022]
Abstract
The efficacy of cisplatin (CIS) and 5-fluorouracil (5-FU) against squamous cell carcinomas of the head and neck (SCCHN) remains restricted due to their severe toxic side effects on non-cancer (normal) tissues. Recently, the broccoli extract sulforaphane (SF) was successfully tested as a combination therapy to target cancer cells. However, the effect of lower doses of CIS or 5-FU combined with SF on SCCHN remained unknown. This study tested the chemotherapeutic efficacies of SF combined with much lower doses of CIS or 5-FU against SCCHN cells aiming to reduce cytotoxicity to normal cells. Titrations of SF standalone or in combination with CIS and 5-FU were tested on SCCHN human cell lines (SCC12 and SCC38) and non-cancerous human cells (fibroblasts, gingival, and salivary cells). Concentrations of SF tested were comparable to those found in the plasma following ingestion of fresh broccoli sprouts. The treatment effects on cell viability, proliferation, DNA damage, apoptosis, and gene expression were measured. SF reduced SCCHN cell viability in a time- and dose-dependent manner. SF-combined treatment increased the cytotoxic activity of CIS by twofolds and of 5-FU by tenfolds against SCCHN, with no effect on non-cancerous cells. SF-combined treatment inhibited SCCHN cell clonogenicity and post-treatment DNA repair. SF increased SCCHN apoptosis and this mechanism was due to a down-regulation of BCL2 and up-regulation of BAX, leading to an up-regulation of Caspase3. In conclusion, combining SF with low doses of CIS or 5-FU increased cytotoxicity against SCCHN cells, while having minimal effects on normal cells.
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Affiliation(s)
- Osama A Elkashty
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, 3640 University Street, Montreal, QC, H3A 0C7, Canada.,Oral Pathology Department, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
| | - Ramy Ashry
- Oral Pathology Department, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
| | - Ghada Abu Elghanam
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, 3640 University Street, Montreal, QC, H3A 0C7, Canada.,Faculty of Medicine, University of Jordan, Amman, Jordan
| | - Hieu M Pham
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, 3640 University Street, Montreal, QC, H3A 0C7, Canada
| | - Xinyun Su
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, 3640 University Street, Montreal, QC, H3A 0C7, Canada.,College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
| | - Camille Stegen
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.,Microbiome and Disease Tolerance Center, McGill University, Montreal, QC, Canada
| | - Simon D Tran
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, 3640 University Street, Montreal, QC, H3A 0C7, Canada.
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Pan Z, Ding Q, Guo Q, Guo Y, Wu L, Wu L, Tang M, Yu H, Zhou F. MORC2, a novel oncogene, is upregulated in liver cancer and contributes to proliferation, metastasis and chemoresistance. Int J Oncol 2018; 53:59-72. [PMID: 29620211 PMCID: PMC5958890 DOI: 10.3892/ijo.2018.4333] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 03/22/2018] [Indexed: 12/20/2022] Open
Abstract
Microrchidia 2 (MORC2) is important in DNA damage repair and lipogenesis, however, the clinical and functional role of MORC2 in liver cancer remains to be fully elucidated. The aim the present study was to clarify the role of MORC2 in liver cancer. Expression profile analysis, immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction analysis and western blot analysis were performed to evaluate the levels of MORC2 in liver cancer patient specimens and cell lines; subsequently the expression of MORC2 was suppressed or increased in liver cancer cells and the effects of MORC2 on the cancerous transformation of liver cancer cells were examined in vitro and in vivo. MORC2 was upregulated in liver cancer tissues, and the upregulation was associated with certain clinicopathologic features of patients with liver cancer. MORC2 knockdown caused marked inhibition of liver cancer cell proliferation and clonogenicity, whereas the overexpression of MORC2 substantially promoted liver cancer cell proliferation. In addition, the knockdown of MORC2 inhibited the migratory and invasive ability of liver cancer cells, whereas increased migration and invasion rates were observed in cells with ectopic expression of MORC2. In a model of nude mice, the overexpression of MORC2 promoted tumorigenicity and markedly enhanced pulmonary metastasis of liver cancer. Furthermore, MORC2 regulated apoptosis and its expression level had an effect on the sensitivity of liver cancer cells to doxorubicin, 5-fluorouracil and cisplatin. Mechanically, MORC2 modulated the mitochondrial apoptotic pathway, possibly in a p53-dependent manner, and its dysregulation also resulted in the abnormal activation of the Hippo pathway. For the first time, to the best of our knowledge, the present study confirmed that MORC2 was a novel oncogene in liver cancer. These results provide useful insight into the mechanism underlying the tumorigenesis and progression of liver cancer, and offers clues into potential novel liver cancer therapies.
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Affiliation(s)
- Zhihong Pan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060
| | - Qianshan Ding
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060
| | - Qian Guo
- Hepatic Disease Institute, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei 430061
| | - Yong Guo
- College of Biotechnology, Guilin Medical University, Guilin, Guanxi 541004
| | - Lianlian Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060
| | - Lu Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060
| | - Meng Tang
- Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Honggang Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060
| | - Fuxiang Zhou
- Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China
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Hong S, Li X, Zhao Y, Yang Q, Kong B. 53BP1 inhibits the migration and regulates the chemotherapy resistance of ovarian cancer cells. Oncol Lett 2018; 15:9917-9922. [PMID: 29928364 DOI: 10.3892/ol.2018.8596] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 05/19/2017] [Indexed: 02/05/2023] Open
Abstract
The major problems faced during the treatment of ovarian cancer are metastasis and the development of intrinsic or acquired drug resistance. The present study assessed whether tumor protein p53 binding protein 1 (53BP1) regulated migration and modulated chemotherapy resistance in SKOV3 cells and identified proteins associated with the molecular mechanisms underlying this coordinate regulation. SKOV3 cells were transfected using a 53BP1-expressing vector, which induced 53BP1 overexpression. The migration of the transfected cells was observed using a Transwell assay. The expression of matrix metalloproteinase (MMP)-2 and MMP-9 were assayed using gelatin zymography. In addition, the effects of 53BP1 on the chemosensitivity of SKOV3 cells to cisplatin were evaluated using MTT and western blot assays. Compared with the control, the average number of migrating SKOV3/pLPC-53BP1 cells was decreased from 230±58 to 45±12 (P<0.05) and the protein expression of MMP-9 was significantly inhibited. However, the chemosensitivity of SKOV3/pLPC-53BP1 to cisplatin decreased significantly: Cisplatin half maximal inhibitory concentration (IC50) for SKOV3/pLPC-53BP1=7.58±0.51 µg/ml; cisplatin IC50 for control=2.98±0.27 µg/ml (P<0.01). Decreased chemosensitivity to cisplatin may be associated with increased expression of phosphorylated-protein kinase B and cyclin dependent kinase 2 and with decreased expression of p21 and the B cell lymphoma (Bcl)-2 associated X/Bcl-2 ratio. The results of the present study demonstrated that 53BP1 may inhibit migration but upregulate chemoresistance to cisplatin in SKOV3 cells.
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Affiliation(s)
- Shuhui Hong
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.,Department of Gynecology, Affiliated Qianfoshan Hospital of Shandong University, Jinan, Shandong 250014, P.R. China
| | - Xiaoyan Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Ying Zhao
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Qifeng Yang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
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Identification of new inhibitors against human Great wall kinase using in silico approaches. Sci Rep 2018; 8:4894. [PMID: 29559668 PMCID: PMC5861128 DOI: 10.1038/s41598-018-23246-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 03/06/2018] [Indexed: 12/18/2022] Open
Abstract
Microtubule associated serine/threonine kinase (MASTL) is an important Ser/Thr kinase belonging to the family of AGC kinases. It is the human orthologue of Greatwall kinase (Gwl) that plays a significant role in mitotic progression and cell cycle regulation. Upregulation of MASTL in various cancers and its association with poor patient survival establishes it as an important drug target in cancer therapy. Nevertheless, the target remains unexplored with the paucity of studies focused on identification of inhibitors against MASTL, which emphasizes the relevance of our present study. We explored various drug databases and performed virtual screening of compounds from both natural and synthetic sources. A list of promising compounds displaying high binding characteristics towards MASTL protein is reported. Among the natural compounds, we found a 6-hydroxynaphthalene derivative ZINC85597499 to display best binding energy value of −9.32 kcal/mol. While among synthetic compounds, a thieno-pyrimidinone based tricyclic derivative ZINC53845290 compound exhibited best binding affinity of value −7.85 kcal/mol. MASTL interactions with these two compounds were further explored using molecular dynamics simulations. Altogether, this study identifies potential inhibitors of human Gwl kinase from both natural and synthetic origin and calls for studying these compounds as potential drugs for cancer therapy.
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45
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Luong KV, Wang L, Roberts BJ, Wahl JK, Peng A. Cell fate determination in cisplatin resistance and chemosensitization. Oncotarget 2018; 7:23383-94. [PMID: 26993599 PMCID: PMC5029634 DOI: 10.18632/oncotarget.8110] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 02/28/2016] [Indexed: 01/22/2023] Open
Abstract
Understanding the determination of cell fate choices after cancer treatment will shed new light on cancer resistance. In this study, we quantitatively analyzed the individual cell fate choice in resistant UM-SCC-38 head and neck cancer cells exposed to cisplatin. Our study revealed a highly heterogeneous pattern of cell fate choices in UM-SCC-38 cells, in comparison to that of the control, non-tumorigenic keratinocyte HaCaT cells. In both UM-SCC-38 and HaCaT cell lines, the majority of cell death occurred during the immediate interphase without mitotic entry, whereas significant portions of UM-SCC-38 cells survived the treatment via either checkpoint arrest or checkpoint slippage. Interestingly, checkpoint slippage occurred predominantly in cells treated in late S and G2 phases, and cells in M-phase were hypersensitive to cisplatin. Moreover, although the cisplatin-resistant progression of mitosis exhibited no delay in general, prolonged mitosis was correlated with the induction of cell death in mitosis. The finding thus suggested a combinatorial treatment using cisplatin and an agent that blocks mitotic exit. Consistently, we showed a strong synergy between cisplatin and the proteasome inhibitor Mg132. Finally, targeting the DNA damage checkpoint using inhibitors of ATR, but not ATM, effectively sensitized UM-SCC-38 to cisplatin treatment. Surprisingly, checkpoint targeting eliminated both checkpoint arrest and checkpoint slippage, and augmented the induction of cell death in interphase without mitotic entry. Taken together, our study, by profiling cell fate determination after cisplatin treatment, reveals new insights into chemoresistance and suggests combinatorial strategies that potentially overcome cancer resistance.
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Affiliation(s)
- Khanh V Luong
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583, USA
| | - Ling Wang
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583, USA
| | - Brett J Roberts
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583, USA
| | - James K Wahl
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583, USA
| | - Aimin Peng
- Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583, USA
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Zhao X, Guo X, Xing L, Yue W, Yin H, He M, Wang J, Yang J, Chen J. HBV infection potentiates resistance to S-phase arrest-inducing chemotherapeutics by inhibiting CHK2 pathway in diffuse large B-cell lymphoma. Cell Death Dis 2018; 9:61. [PMID: 29352124 PMCID: PMC5833392 DOI: 10.1038/s41419-017-0097-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/23/2017] [Accepted: 10/23/2017] [Indexed: 12/15/2022]
Abstract
A considerable number of diffuse large B-cell lymphoma (DLBCL) patients are infected with hepatitis B virus (HBV), which is correlated with their poor outcomes. However, the role of HBV infection in DLBCL treatment failure remains poorly understood. Here, our data demonstrated that HBV infection was closely associated with poorer clinical prognosis independent of its hepatic dysfunction in germinal center B-cell type (GCB type) DLBCL patients. Interestingly, we found that DLBCL cells expressing hepatitis B virus X protein (HBX) did not exhibit enhanced cell growth but did show reduced sensitivity to methotrexate (MTX) and cytarabine (Ara-C), which induced S-phase arrest. Mechanism studies showed that HBX specifically inhibited the phosphorylation of checkpoint kinase 2 (CHK2, a key DNA damage response protein). CHK2 depletion similarly conferred resistance to the S-phase arrest-inducing chemotherapeutics, consistent with HBX overexpression in DLBCL cells. Moreover, overexpression of wild-type CHK2 rather than its unphosphorylated mutant (T68A) significantly restored the reduced chemosensitivity in HBX-expressing cells, suggesting that HBV infection conferred resistance to chemotherapeutics that induced S-phase arrest by specifically inhibiting the activation of CHK2 response signaling in DLBCL.
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Affiliation(s)
- Xinying Zhao
- Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China.,Department of Hematology, Jingzhou Central Hospital, Jingzhou Clinical Medical College, Yangtze University, Jingzhou, China
| | - Xudong Guo
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, Shanghai, China.,Institute of Regenerative Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Libo Xing
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, Shanghai, China
| | - Wenqin Yue
- Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Haisen Yin
- Department of Hematology, Jingzhou Central Hospital, Jingzhou Clinical Medical College, Yangtze University, Jingzhou, China
| | - Miaoxia He
- Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jianmin Wang
- Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jianmin Yang
- Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jie Chen
- Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China.
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Norouzi-Barough L, Sarookhani MR, Sharifi M, Moghbelinejad S, Jangjoo S, Salehi R. Molecular mechanisms of drug resistance in ovarian cancer. J Cell Physiol 2018; 233:4546-4562. [PMID: 29152737 DOI: 10.1002/jcp.26289] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 11/14/2017] [Indexed: 12/13/2022]
Abstract
Ovarian cancer is the most lethal malignancy among the gynecological cancers, with a 5-year survival rate, mainly due to being diagnosed at advanced stages, recurrence and resistance to the current chemotherapeutic agents. Drug resistance is a complex phenomenon and the number of known involved genes and cross-talks between signaling pathways in this process is growing rapidly. Thus, discovering and understanding the underlying molecular mechanisms involved in chemo-resistance are crucial for management of treatment and identifying novel and effective drug targets as well as drug discovery to improve therapeutic outcomes. In this review, the major and recently identified molecular mechanisms of drug resistance in ovarian cancer from relevant literature have been investigated. In the final section of the paper, new approaches for studying detailed mechanisms of chemo-resistance have been briefly discussed.
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Affiliation(s)
- Leyla Norouzi-Barough
- Department of Molecular Medicine, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Mohammadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sahar Moghbelinejad
- Department of Biochemistry and Genetic, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Saranaz Jangjoo
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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48
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Abstract
Cancer is a daunting global problem confronting the world's population. The most frequent therapeutic approaches include surgery, chemotherapy, radiotherapy, and more recently immunotherapy. In the case of chemotherapy, patients ultimately develop resistance to both single and multiple chemotherapeutic agents, which can culminate in metastatic disease which is a major cause of patient death from solid tumors. Chemoresistance, a primary cause of treatment failure, is attributed to multiple factors including decreased drug accumulation, reduced drug-target interactions, increased populations of cancer stem cells, enhanced autophagy activity, and reduced apoptosis in cancer cells. Reprogramming tumor cells to undergo drug-induced apoptosis provides a promising and powerful strategy for treating resistant and recurrent neoplastic diseases. This can be achieved by downregulating dysregulated antiapoptotic factors or activation of proapoptotic factors in tumor cells. A major target of dysregulation in cancer cells that can occur during chemoresistance involves altered expression of Bcl-2 family members. Bcl-2 antiapoptotic molecules (Bcl-2, Bcl-xL, and Mcl-1) are frequently upregulated in acquired chemoresistant cancer cells, which block drug-induced apoptosis. We presently overview the potential role of Bcl-2 antiapoptotic proteins in the development of cancer chemoresistance and overview the clinical approaches that use Bcl-2 inhibitors to restore cell death in chemoresistant and recurrent tumors.
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49
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Zheng HC. The molecular mechanisms of chemoresistance in cancers. Oncotarget 2017; 8:59950-59964. [PMID: 28938696 PMCID: PMC5601792 DOI: 10.18632/oncotarget.19048] [Citation(s) in RCA: 455] [Impact Index Per Article: 56.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 06/24/2017] [Indexed: 12/11/2022] Open
Abstract
Overcoming intrinsic and acquired drug resistance is a major challenge in treating cancer patients because chemoresistance causes recurrence, cancer dissemination and death. This review summarizes numerous molecular aspects of multi-resistance, including transporter pumps, oncogenes (EGFR, PI3K/Akt, Erk and NF-κB), tumor suppressor gene (p53), mitochondrial alteration, DNA repair, autophagy, epithelial-mesenchymal transition (EMT), cancer stemness, and exosome. The chemoresistance-related proteins are localized to extracellular ligand, membrane receptor, cytosolic signal messenger, and nuclear transcription factors for various events, including proliferation, apoptosis, EMT, autophagy and exosome. Their cross-talk frequently appears, such as the regulatory effects of EGFR-Akt-NF-κB signal pathway on the transcription of Bcl-2, Bcl-xL and survivin or EMT-related stemness. It is essential for the realization of the target, individualized and combine therapy to clarify these molecular mechanisms, explore the therapy target, screen chemosensitive population, and determine the efficacy of chemoreagents by cell culture and orthotopic model.
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Affiliation(s)
- Hua-Chuan Zheng
- Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China
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50
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Regulatory players of DNA damage repair mechanisms: Role in Cancer Chemoresistance. Biomed Pharmacother 2017; 93:1238-1245. [PMID: 28738540 DOI: 10.1016/j.biopha.2017.07.035] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 06/28/2017] [Accepted: 07/06/2017] [Indexed: 11/20/2022] Open
Abstract
DNA damaging agents are most common in chemotherapeutic molecules that act against cancer. However, cancer cells possess inherent biological features to overcome DNA damages by activating various distinct repair mechanisms and pathways. Importantly, various oncogenes, cancer stem cells (CSCs), hypoxic environment, transcription factors and bystander signaling that are activated in the cancer cells influence DNA repair, thereby effectively repairing the DNA damage. Repaired cancer cells often become more resistance to further therapy and results in disease recurrence. In this review, we summarize how the various signaling pathways in cancer cells regulates DNA repair and induce chemoresistance.
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