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Hazra R, Chattopadhyay S, Mallick A, Gayen S, Roy S. Unravelling CD24-Siglec-10 pathway: Cancer immunotherapy from basic science to clinical studies. Immunology 2024; 173:442-469. [PMID: 39129256 DOI: 10.1111/imm.13847] [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: 03/22/2024] [Accepted: 07/27/2024] [Indexed: 08/13/2024] Open
Abstract
Cancer immunotherapy has revolutionized the treatment landscape by harnessing the power of the immune system to combat malignancies. Two of the most promising players in this field are cluster of differentiation 24 (CD24) and sialic acid-binding Ig-like lectin 10 (Siglec-10), and both of them play pivotal roles in modulating immune responses. CD24, a cell surface glycoprotein, emerges as a convincing fundamental signal transducer for therapeutic intervention, given its significant implication in the processes related to tumour progression and immunogenic evasion. Additionally, the immunomodulatory functions of Siglec-10, a prominent member within the Siglec family of immune receptors, have recently become a crucial point of interest, particularly in the context of the tumour microenvironment. Hence, the intricate interplay of both CD24 and Siglec-10 assumes a critical role in fostering tumour growth, facilitating metastasis and also orchestrating immune evasion. Recent studies have found multiple evidences supporting the therapeutic potential of targeting CD24 in cancer treatment. Siglec-10, on the other hand, exhibits immunosuppressive properties that contribute to immune tolerance within the tumour microenvironment. Therefore, we delve into the complex mechanisms through which Siglec-10 modulates immune responses and facilitates immune escape in cancer. Siglec-10 also acts as a viable target for cancer immunotherapy and presents novel avenues for the development of therapeutic interventions. Furthermore, we examine the synergy between CD24 and Siglec-10 in shaping the immunosuppressive tumour microenvironment and discuss the implications for combination therapies. Therefore, understanding the roles of CD24 and Siglec-10 in cancer immunotherapy opens exciting possibilities for the development of novel therapeutics.
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Affiliation(s)
- Rudradeep Hazra
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Soumyadeep Chattopadhyay
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Arijit Mallick
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Sakuntala Gayen
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
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2
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Kojima K, Konishi H, Momosaki K, Komatani Y, Katsuyama A, Nakagawa K, Kanamitsu K, Yakushiji F, Fujiya M, Ichikawa S. Synthesis and biological evaluation of echinomycin analogues as potential colon cancer agent. Sci Rep 2024; 14:7628. [PMID: 38561454 PMCID: PMC10985088 DOI: 10.1038/s41598-024-58196-3] [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: 12/08/2023] [Accepted: 03/26/2024] [Indexed: 04/04/2024] Open
Abstract
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death, thus a novel chemotherapeutic agent for colon cancer therapy is needed. In this study, analogues of echinomycin, a cyclic peptide natural product with potent toxicity to several human cancer cell lines, were synthesized, and their biological activities against human colon cancer cells were investigated. Analogue 3 as well as 1 inhibit HIF-1α-mediated transcription. Notably, transcriptome analysis indicated that the cell cycle and its regulation were involved in the effects on cells treated with 3. Analogue 3 exhibited superior in vivo efficacy to echinomycin without significant toxicity in mouse xenograft model. The low dose of 3 needed to be efficacious in vivo is also noteworthy and our data suggest that 3 is an attractive and potentially novel agent for the treatment of colon cancer.
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Affiliation(s)
- Keita Kojima
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan
| | - Hiroaki Konishi
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Asahikawa, Hokkaido, 078-8510, Japan
| | - Kyoka Momosaki
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan
| | - Yuya Komatani
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan
| | - Akira Katsuyama
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan
- Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan
- Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Sapporo, 060-0812, Japan
| | - Koji Nakagawa
- School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu-cho, Ishikari-gun, Hokkaido, 061-0293, Japan
| | - Kayoko Kanamitsu
- Lead Exploration Unit, Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Fumika Yakushiji
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan
- Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan
- Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Sapporo, 060-0812, Japan
| | - Mikihiro Fujiya
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Asahikawa, Hokkaido, 078-8510, Japan
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Satoshi Ichikawa
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
- Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
- Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Sapporo, 060-0812, Japan.
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3
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Tewari AB, Saini A, Sharma D. Extirpating the cancer stem cell hydra: Differentiation therapy and Hyperthermia therapy for targeting the cancer stem cell hierarchy. Clin Exp Med 2023; 23:3125-3145. [PMID: 37093450 DOI: 10.1007/s10238-023-01066-5] [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: 12/09/2022] [Accepted: 04/02/2023] [Indexed: 04/25/2023]
Abstract
Ever since the discovery of cancer stem cells (CSCs), they have progressively attracted more attention as a therapeutic target. Like the mythical hydra, this subpopulation of cells seems to contribute to cancer immortality, spawning more cells each time that some components of the cancer cell hierarchy are destroyed. Traditional modalities focusing on cancer treatment have emphasized apoptosis as a route to eliminate the tumor burden. A major problem is that cancer cells are often in varying degrees of dedifferentiation contributing to what is known as the CSCs hierarchy and cells which are known to be resistant to conventional therapy. Differentiation therapy is an experimental therapeutic modality aimed at the conversion of malignant phenotype to a more benign one. Hyperthermia therapy (HT) is a modality exploiting the changes induced in cells by the application of heat produced to aid in cancer therapy. While differentiation therapy has been successfully employed in the treatment of acute myeloid leukemia, it has not been hugely successful for other cancer types. Mounting evidence suggests that hyperthermia therapy may greatly augment the effects of differentiation therapy while simultaneously overcoming many of the hard-to-treat facets of recurrent tumors. This review summarizes the progress made so far in integrating hyperthermia therapy with existing modules of differentiation therapy. The focus is on studies related to the successful application of both hyperthermia and differentiation therapy when used alone or in conjunction for hard-to-treat cancer cell niche with emphasis on combined approaches to target the CSCs hierarchy.
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Affiliation(s)
- Amit B Tewari
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India
| | - Anamika Saini
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India
| | - Deepika Sharma
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India.
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4
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Zhao Y, Qin C, Zhao B, Wang Y, Li Z, Li T, Yang X, Wang W. Pancreatic cancer stemness: dynamic status in malignant progression. J Exp Clin Cancer Res 2023; 42:122. [PMID: 37173787 PMCID: PMC10182699 DOI: 10.1186/s13046-023-02693-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide. Increasing evidence suggests that the capacity for self-renewal, proliferation, and differentiation of pancreatic cancer stem cells (PCSCs) contribute to major challenges with current PC therapies, causing metastasis and therapeutic resistance, leading to recurrence and death in patients. The concept that PCSCs are characterized by their high plasticity and self-renewal capacities is central to this review. We focused specifically on the regulation of PCSCs, such as stemness-related signaling pathways, stimuli in tumor cells and the tumor microenvironment (TME), as well as the development of innovative stemness-targeted therapies. Understanding the biological behavior of PCSCs with plasticity and the molecular mechanisms regulating PC stemness will help to identify new treatment strategies to treat this horrible disease.
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Affiliation(s)
- Yutong Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Bangbo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Yuanyang Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Zeru Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Tianyu Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Xiaoying Yang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China.
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5
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Bhattacharyya S, Ghosh H, Covarrubias-Zambrano O, Jain K, Swamy KV, Kasi A, Hamza A, Anant S, VanSaun M, Weir SJ, Bossmann SH, Padhye SB, Dandawate P. Anticancer Activity of Novel Difluorinated Curcumin Analog and Its Inclusion Complex with 2-Hydroxypropyl-β-Cyclodextrin against Pancreatic Cancer. Int J Mol Sci 2023; 24:ijms24076336. [PMID: 37047307 PMCID: PMC10093935 DOI: 10.3390/ijms24076336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/14/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the primary reason for cancer-related deaths in the US. Genetic mutations, drug resistance, the involvement of multiple signaling pathways, cancer stem cells (CSCs), and desmoplastic stroma, which hinders drug penetrance, contribute to poor chemotherapeutic efficacy. Hence, there is a need to identify novel drugs with improved delivery to improve treatment outcomes. Curcumin is one such compound that can inhibit multiple signaling pathways and CSCs. However, curcumin’s clinical applicability for treating PDAC is limited because of its poor solubility in water and metabolic instability. Hence, we developed a difluorinated curcumin (CDF) analog that accumulates selectively in the pancreas and inhibits PDAC growth in vitro and in vivo. In the present work, we developed its 2-hydroxy-propyl-β-cyclodextrin (HCD) inclusion complex to increase its water solubility and hydrolytic stability. The CDFHCD inclusion complex was characterized by spectroscopic, thermal, and microscopic techniques. The inclusion complex exhibited increased aqueous solubility, hydrolytic stability, and antiproliferative activity compared to parent CDF. Moreover, CDF and CDFHCD inhibited colony and spheroid formation, and induced cell cycle and apoptosis in PDAC cell lines. Hence, CDFHCD self-assembly is an efficient approach to increase water solubility and anticancer therapeutic efficacy, which now warrants advancement towards a clinical proof of concept in PDAC patients.
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Affiliation(s)
- Sangita Bhattacharyya
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Hindole Ghosh
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | | | - Krishan Jain
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - K. Venkateswara Swamy
- MIT School of Bioengineering, Sciences & Research, MIT Art, Design and Technology University, Pune 412201, India
| | - Anup Kasi
- Division of Medical Oncology, University of Kansas, Kansas City, KS 66160, USA
| | - Ameer Hamza
- Pathology and Laboratory Medicine, University of Kansas, Kansas City, KS 66160, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Michael VanSaun
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Scott J. Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
- Division of Medical Oncology, University of Kansas, Kansas City, KS 66160, USA
- Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Stefan H. Bossmann
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Subhash B. Padhye
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
- Interdisciplinary Science & Technology Research Academy (ISTRA), Azam Campus, University of Pune, Pune 411001, India
| | - Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
- Correspondence: ; Tel.: +1-913-945-6336
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6
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Zhuo F, Luo S, He W, Feng Z, Hu Y, Xu J, Wang Z, Xu J. The Role of Signaling Pathways in Pancreatic Cancer Targeted Therapy. Am J Clin Oncol 2023; 46:121-128. [PMID: 36735511 DOI: 10.1097/coc.0000000000000979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Signaling pathways play significant roles in the occurrence, development, and treatment of pancreatic cancer (PC). The main treatment options are surgery, chemotherapy, radiotherapy, arterial infusion chemotherapy in interventional therapy, and immunotherapy. Many studies have shown that signaling pathways perform a function in the occurrence and development of PC, for instance, phosphoinositide 3-kinase (PI3K)/AKT, nuclear factor-κB, Ras, interleukin (IL)-17B/IL-17RB, Wnt, and hepatocyte growth factor/c-MET, which play roles in the proliferation, metastasis, invasion, inhibition of apoptosis, promotion of angiogenesis, and drug resistance of PC. Interaction of signaling pathways has an impact on the biological behavior of PC; for example, activation of the neurotensin/NTSR1 pathway, which can activate mitogen-activated protein kinase, nuclear factor-κB, and other pathways related to PC stem cells, play an important role in PC, and an increase in their number is associated with the Wnt/β-catenin and PI3K pathways. Chemotherapy is the main method for the treatment of PC, but drug resistance limits its use. In addition, abnormal activation of IL-17B/IL-17RB signaling pathway is associated with drug resistance. This article discusses the signaling pathways that play different roles in the occurrence and development of PC, as well as current research on signaling pathways in PC treatment.
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Affiliation(s)
- Fangfang Zhuo
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences)
- Department of Clinical Medical College
| | - Shuang Luo
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences)
- Department of Clinical Medical College
| | - Wei He
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences)
- Department of Clinical Medical College
| | - Zhanhui Feng
- Neurological Department, Affiliated Hospital of Guizhou Medical University
| | - Ya'nan Hu
- Department of Cell Biology, Medical College of Soochow University, Suzhou, China
| | - Jingxia Xu
- Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University
| | - Zejun Wang
- Department of Gastrointestinal Surgery, Affiliated Cancer Hospital of Guizhou Medical University
| | - Jianwei Xu
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences)
- Department of Clinical Medical College
- Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang, China
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7
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Standing D, Arnold L, Dandawate P, Ottemann B, Snyder V, Ponnurangam S, Sayed A, Subramaniam D, Srinivasan P, Choudhury S, New J, Kwatra D, Ramamoorthy P, Roy BC, Shadoin M, Al-Rajabi R, O’Neil M, Gunewardena S, Ashcraft J, Umar S, Weir SJ, Tawfik O, Padhye SB, Biersack B, Anant S, Thomas SM. Doublecortin-like kinase 1 is a therapeutic target in squamous cell carcinoma. Mol Carcinog 2023; 62:145-159. [PMID: 36218231 PMCID: PMC9852063 DOI: 10.1002/mc.23472] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/19/2022] [Accepted: 09/27/2022] [Indexed: 01/25/2023]
Abstract
Doublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck SCC (HNSCC) and anal SCC (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in human papilloma virus negative HNSCC, which are typically aggressive with poor responses to therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on nonspecific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD (3,5-bis [2,4-difluorobenzylidene]-4-piperidone) binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth.
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Affiliation(s)
- David Standing
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Levi Arnold
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Brendan Ottemann
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas
| | - Vusala Snyder
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas
| | - Sivapriya Ponnurangam
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Afreen Sayed
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | | | | | - Sonali Choudhury
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Jacob New
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Deep Kwatra
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Prabhu Ramamoorthy
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Badal C. Roy
- Department of General Surgery, University of Kansas Medical Center, Kansas City, Kansas
| | - Melissa Shadoin
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas
| | - Raed Al-Rajabi
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas
| | - Maura O’Neil
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas
| | - John Ashcraft
- Department of General Surgery, University of Kansas Medical Center, Kansas City, Kansas
| | - Shahid Umar
- Department of General Surgery, University of Kansas Medical Center, Kansas City, Kansas
| | - Scott J. Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
- Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, Kansas
| | - Ossama Tawfik
- Department of Pathology, Saint Luke’s Health System, Kansas City, Missouri and MAWD Pathology Group, Kansas City, Kansas
| | | | | | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Sufi Mary Thomas
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas
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8
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Mukherjee AG, Wanjari UR, Gopalakrishnan AV, Bradu P, Sukumar A, Patil M, Renu K, Dey A, Vellingiri B, George A, Ganesan R. Implications of cancer stem cells in diabetes and pancreatic cancer. Life Sci 2022; 312:121211. [PMID: 36414089 DOI: 10.1016/j.lfs.2022.121211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 11/21/2022]
Abstract
This review provides a detailed study of pancreatic cancer (PC) and the implication of different types of cancers concerning diabetes. The combination of anti-diabetic drugs with other anti-cancer drugs and phytochemicals can help prevent and treat this disease. PC cancer stem cells (CSCs) and how they migrate and develop into malignant tumors are discussed. A detailed explanation of the different mechanisms of diabetes development, which can enhance the pancreatic CSCs' proliferation by increasing the IGF factor levels, epigenetic modifications, DNA damage, and the influence of lifestyle factors like obesity, and inflammation, has been discussed. It also explains how cancer due to diabetes is associated with high mortality rates. One of the well-known diabetic drugs, metformin, can be combined with other anti-cancer drugs and prevent the development of PC and has been taken as one of the prime focus in this review. Overall, this paper provides insight into the relationship between diabetes and PC and the methods that can be employed to diagnose this disease at an earlier stage successfully.
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Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
| | - Pragya Bradu
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Aarthi Sukumar
- Department of Integrative Biology, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Megha Patil
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, Tamil Nadu, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, West Bengal, 700073, India
| | - Balachandar Vellingiri
- Stem cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda - 151401, Punjab, India
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur, 680005, Kerala, India
| | - Raja Ganesan
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, 24252, Republic of Korea
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9
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Current Opportunities for Targeting Dysregulated Neurodevelopmental Signaling Pathways in Glioblastoma. Cells 2022; 11:cells11162530. [PMID: 36010607 PMCID: PMC9406959 DOI: 10.3390/cells11162530] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/06/2022] [Accepted: 08/09/2022] [Indexed: 11/29/2022] Open
Abstract
Glioblastoma (GBM) is the most common and highly lethal type of brain tumor, with poor survival despite advances in understanding its complexity. After current standard therapeutic treatment, including tumor resection, radiotherapy and concomitant chemotherapy with temozolomide, the median overall survival of patients with this type of tumor is less than 15 months. Thus, there is an urgent need for new insights into GBM molecular characteristics and progress in targeted therapy in order to improve clinical outcomes. The literature data revealed that a number of different signaling pathways are dysregulated in GBM. In this review, we intended to summarize and discuss current literature data and therapeutic modalities focused on targeting dysregulated signaling pathways in GBM. A better understanding of opportunities for targeting signaling pathways that influences malignant behavior of GBM cells might open the way for the development of novel GBM-targeted therapies.
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10
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V. Bala Aakash, Ramalakshmi N, Bhuvaneswari S, Sankari E, Arunkumar S. Comprehensive Review on Versatile Pharmacology of Quinoxaline Derivative. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2022. [DOI: 10.1134/s1068162022040069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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11
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Samanta S, Mahata R, Santra MK. The Cross-Talk between Epigenetic Gene Regulation and Signaling Pathways Regulates Cancer Pathogenesis. Subcell Biochem 2022; 100:427-472. [PMID: 36301502 DOI: 10.1007/978-3-031-07634-3_13] [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] [Indexed: 06/16/2023]
Abstract
Cancer begins due to uncontrolled cell division. Cancer cells are insensitive to the signals that control normal cell proliferation. This uncontrolled cell division is due to the accumulation of abnormalities in different factors associated with the cell division, including different cyclins, cell cycle checkpoint inhibitors, and cellular signaling. Cellular signaling pathways are aberrantly activated in cancer mainly due to epigenetic regulation and post-translational regulation. In this chapter, the role of epigenetic regulation in aberrant activation of PI3K/AKT, Ras, Wnt, Hedgehog, Notch, JAK/STAT, and mTOR signaling pathways in cancer progression is discussed. The role of epigenetic regulators in controlling the upstream regulatory proteins and downstream effector proteins responsible for abnormal cellular signaling-mediated cancer progression is covered in this chapter. Similarly, the role of signaling pathways in controlling epigenetic gene regulation-mediated cancer progression is also discussed. We have tried to ascertain the current status of potential epigenetic drugs targeting several epigenetic regulators to prevent different cancers.
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Affiliation(s)
- Snigdha Samanta
- Molecular Oncology Laboratory, National Centre for Cell Science, NCCS Complex, S. P. Pune University Campus, Ganeshkhind Road, Pune, Maharashtra, India
- Department of Biotechnology, Savitribai Phule Pune University, Pune, Maharashtra, India
| | - Rumpa Mahata
- Molecular Oncology Laboratory, National Centre for Cell Science, NCCS Complex, S. P. Pune University Campus, Ganeshkhind Road, Pune, Maharashtra, India
- Department of Biotechnology, Savitribai Phule Pune University, Pune, Maharashtra, India
| | - Manas Kumar Santra
- Molecular Oncology Laboratory, National Centre for Cell Science, NCCS Complex, S. P. Pune University Campus, Ganeshkhind Road, Pune, Maharashtra, India.
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12
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Wang Y, Yi J, Liu X. Roles of Dclk1 in the pathogenesis, diagnosis, prognosis and treatment of pancreatic cancer: A review. Expert Rev Gastroenterol Hepatol 2022; 16:13-19. [PMID: 34937474 DOI: 10.1080/17474124.2022.2020643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 12/16/2021] [Indexed: 11/11/2022]
Abstract
INTRODUCTION Pancreatic cancer (PC) is a malignant tumor with significantly increased incidence and poor prognosis. Its extremely poor prognosis is generally attributed to its early invasion and metastasis as well as the presence of chemotherapy resistance, which may be related to the potential role of cancer stem cells (CSCs). Doublecortin-like kinase 1 (Dclk1) has been recognized to be a marker of CSCs in PC, showing intimate association with its occurrence, metastasis, and poor prognosis. AREAS COVERED A review serves to provide a comprehensive overview of Dclk1 in the pathogenesis, diagnosis, prognosis, and treatment in PC. EXPERT OPINION Searching for potential key biomarkers for PC has been an urgent issue to be addressed. The expression of Dclk1 is increasing in PC, and its effect is linked to the mutant Kras, supporting that it may be a potential new target. Therefore, it highlights Dclk1 as a candidate biomarker and therapeutic target in future clinical application.
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Affiliation(s)
- Yifan Wang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Jun Yi
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
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13
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Chen C, Chen X, Ren B, Guo H, Abdel-Mageed WM, Liu X, Song F, Zhang L. Characterization of Streptomyces sp. LS462 with high productivity of echinomycin, a potent antituberculosis and synergistic antifungal antibiotic. J Ind Microbiol Biotechnol 2021; 48:kuab079. [PMID: 34661655 PMCID: PMC8788810 DOI: 10.1093/jimb/kuab079] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 10/12/2021] [Indexed: 02/05/2023]
Abstract
A biologically active microbial strain, designated as "LS462," was isolated from a soil sample collected from Yaoli Virgin Forest of Jiangxi Province, China. The strain was able to produce a high yield of echinomycin (172 mg/l) even under nonoptimized culture conditions and is proposed to serve as a promising source of echinomycin. In this study, echinomycin exhibited strong anti-Mycobacterium tuberculosis H37Rv activity and synergistic antifungal effect with a greatly reduced dosage of posaconazole on Candida albicans SC5314. The strain belongs to the genus Streptomyces according to its morphological and 16S rDNA phylogenetic analysis. The 16S rDNA was found to have the highest sequence identity with Streptomyces fuscichromogenes (99.37% similarity). Extensive nuclear magnetic resonance and mass spectroscopic data were used to determine the structure of echinomycin. The strain S. fuscichromogenes has not been previously reported to produce echinomycin. Strain LS462 may be exploited as a new potential source for the commercial production of echinomycin. Also, this work is the first to report the new synergistic antifungal activity of echinomycin and further study of the synergistic mechanism will be helpful to guide the development of antifungal agents.
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Affiliation(s)
- Caixia Chen
- Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, P. R. China
- School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Xiangyin Chen
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, P. R. China
| | - Biao Ren
- Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, P. R. China
- West China Hospital of Stomatology, Sichuan University, Sichuan 610041, P. R. China
| | - Hui Guo
- Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, P. R. China
- Institute of Biophysics, Chinese Academy of Sciences, Beijing 100190, P. R. China
| | - Wael M Abdel-Mageed
- Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, P. R. China
- Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Xueting Liu
- Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, P. R. China
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, P. R. China
| | - Fuhang Song
- Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, P. R. China
- School of Light Industry, Beijing Technology and Business University, Beijing 100048, P. R. China
| | - Lixin Zhang
- Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, P. R. China
- State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, P. R. China
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14
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Singh D, Mohapatra P, Kumar S, Behera S, Dixit A, Sahoo SK. Nimbolide-encapsulated PLGA nanoparticles induces Mesenchymal-to-Epithelial Transition by dual inhibition of AKT and mTOR in pancreatic cancer stem cells. Toxicol In Vitro 2021; 79:105293. [PMID: 34883246 DOI: 10.1016/j.tiv.2021.105293] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 11/17/2021] [Accepted: 12/01/2021] [Indexed: 12/30/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and remains highly aggressive despite current advancements in therapies. Chemoresistance and high metastatic nature of PDAC is attributed to a small subset of stem-like cells within the tumor known as Cancer Stem Cells (CSCs). Here, we developed a strategy for targeting pancreatic CSCs through forceful induction of mesenchymal-to-epithelial transition driven by encapsulating a phytochemical Nimbolide in nanoparticles. Binding of Nimbolide with the key regulator proteins of CSCs were studied through molecular docking and molecular dynamic simulation studies, which revealed that it binds to AKT and mTOR with high affinity. Further, in vitro studies revealed that Nim NPs are capable of inducing forceful mesenchymal-to-epithelial transition of pancreatospheres that leads to loss of multidrug resistance and self-renewal properties of pancreatospheres. Our study gives a proof of concept that encapsulation of Nim in PLGA nanoparticles increases its therapeutic effect on pancreatospheres. Further, binding of Nim to AKT and mTOR negatively regulates their activity that ultimately leads to mesenchymal-to-epithelial transition of pancreatic CSCs.
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Affiliation(s)
- Deepika Singh
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
| | - Priyanka Mohapatra
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India; Regional Centre for Biotechnology, Faridabad 121001, Haryana, India
| | - Sugandh Kumar
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
| | - Somalisa Behera
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
| | - Anshuman Dixit
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
| | - Sanjeeb Kumar Sahoo
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India.
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15
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Patil K, Khan FB, Akhtar S, Ahmad A, Uddin S. The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance. Cancer Metastasis Rev 2021; 40:691-720. [PMID: 34453639 PMCID: PMC8556195 DOI: 10.1007/s10555-021-09979-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ''tumor debulking'' rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting 'natural agents' that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.
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Affiliation(s)
- Kalyani Patil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Farheen B Khan
- Department of Biology, College of Science, The United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates
| | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
- Laboratory Animal Research Center, Qatar University, Doha, Qatar.
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16
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Radadiya PS, Thornton MM, Daniel EA, Idowu JY, Wang W, Magenheimer B, Subramaniam D, Tran PV, Calvet JP, Wallace DP, Sharma M. Quinomycin A reduces cyst progression in polycystic kidney disease. FASEB J 2021; 35:e21533. [PMID: 33826787 PMCID: PMC8251518 DOI: 10.1096/fj.202002490r] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/11/2021] [Accepted: 03/01/2021] [Indexed: 12/11/2022]
Abstract
Polycystic kidney disease (PKD) is a genetic disorder characterized by aberrant renal epithelial cell proliferation and formation and progressive growth of numerous fluid-filled cysts within the kidneys. Previously, we showed that there is elevated Notch signaling compared to normal renal epithelial cells and that Notch signaling contributes to the proliferation of cystic cells. Quinomycin A, a bis-intercalator peptide, has previously been shown to target the Notch signaling pathway and inhibit tumor growth in cancer. Here, we show that Quinomycin A decreased cell proliferation and cyst growth of human ADPKD cyst epithelial cells cultured within a 3D collagen gel. Treatment with Quinomycin A reduced kidney weight to body weight ratio and decreased renal cystic area and fibrosis in Pkd1RC/RC ; Pkd2+/- mice, an orthologous PKD mouse model. This was accompanied by reduced expression of Notch pathway proteins, RBPjk and HeyL and cell proliferation in kidneys of PKD mice. Quinomycin A treatments also normalized cilia length of cyst epithelial cells derived from the collecting ducts. This is the first study to demonstrate that Quinomycin A effectively inhibits PKD progression and suggests that Quinomycin A has potential therapeutic value for PKD patients.
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Affiliation(s)
- Priyanka S Radadiya
- Departments of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.,The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Mackenzie M Thornton
- Departments of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.,The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Emily A Daniel
- Departments of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.,The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Jessica Y Idowu
- Departments of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.,The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Wei Wang
- Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.,The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Brenda Magenheimer
- Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA.,The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | | | - Pamela V Tran
- Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.,The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - James P Calvet
- Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA.,The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Darren P Wallace
- Departments of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.,The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Madhulika Sharma
- Departments of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
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17
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Farder-Gomes CF, Fernandes KM, Bernardes RC, Bastos DSS, Martins GF, Serrão JE. Acute exposure to fipronil induces oxidative stress, apoptosis and impairs epithelial homeostasis in the midgut of the stingless bee Partamona helleri Friese (Hymenoptera: Apidae). THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 774:145679. [PMID: 33611004 DOI: 10.1016/j.scitotenv.2021.145679] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 06/12/2023]
Abstract
Partamona helleri is an important pollinator in natural and agricultural ecosystems in the neotropics. However, the foraging activity of this bee increases its risk of exposure to pesticides, which may affect both the individuals and the colony. Thus, this study aims to evaluate the side effects of LC50 of fipronil (0.28 ng a.i. μL-1) on the midgut morphology, antioxidant activity and some pathways of cell death, proliferation and differentiation in workers of P. helleri, after 24 h of oral exposure. Fipronil caused morphological alterations in the midgut of the bees. The activities of the detoxification enzymes superoxide dismutase, catalase and glutathione S-transferase increased after exposure, which suggests the occurrence of a detoxification mechanism. Furthermore, exposure to fipronil changed the number of positive cells for signaling-pathway proteins in the midgut of bees, which indicates the induction of cell death by the apoptotic pathway and impairment of the midgut epithelial regeneration. These results demonstrate that fipronil may negatively affect the morphology and physiology of the midgut of the stingless bee P. helleri and impose a threat to the survival of non-target organisms.
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Affiliation(s)
| | - Kenner Morais Fernandes
- Department of General Biology, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
| | | | - Daniel Silva Sena Bastos
- Department of General Biology, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
| | - Gustavo Ferreira Martins
- Department of General Biology, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil.
| | - José Eduardo Serrão
- Department of General Biology, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil.
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18
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Thakur G, Kumar R, Kim SB, Lee SY, Lee SL, Rho GJ. Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma. Biomedicines 2021; 9:biomedicines9020178. [PMID: 33670230 PMCID: PMC7916947 DOI: 10.3390/biomedicines9020178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine's action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.
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Affiliation(s)
- Gitika Thakur
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Raj Kumar
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173 234, Himachal Pradesh, India;
| | - Saet-Byul Kim
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sang-Yeob Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sung-Lim Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
- Correspondence:
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19
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Majumder S, Crabtree JS, Golde TE, Minter LM, Osborne BA, Miele L. Targeting Notch in oncology: the path forward. Nat Rev Drug Discov 2021; 20:125-144. [PMID: 33293690 DOI: 10.1038/s41573-020-00091-3] [Citation(s) in RCA: 170] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2020] [Indexed: 02/07/2023]
Abstract
Notch signalling is involved in many aspects of cancer biology, including angiogenesis, tumour immunity and the maintenance of cancer stem-like cells. In addition, Notch can function as an oncogene and a tumour suppressor in different cancers and in different cell populations within the same tumour. Despite promising preclinical results and early-phase clinical trials, the goal of developing safe, effective, tumour-selective Notch-targeting agents for clinical use remains elusive. However, our continually improving understanding of Notch signalling in specific cancers, individual cancer cases and different cell populations, as well as crosstalk between pathways, is aiding the discovery and development of novel investigational Notch-targeted therapeutics.
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Affiliation(s)
- Samarpan Majumder
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Judy S Crabtree
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Todd E Golde
- Department of Neuroscience, University of Florida, Gainesville, FL, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Lisa M Minter
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, USA
| | - Barbara A Osborne
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, USA
| | - Lucio Miele
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
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20
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Wu LH, Zhou S, Luo QF, Tian JS, Loh TP. Dichloroacetophenone Derivatives: A Class of Bioconjugation Reagents for Disulfide Bridging. Org Lett 2020; 22:8193-8197. [PMID: 33052688 DOI: 10.1021/acs.orglett.0c02477] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A mild and biocompatible method for the construction of disulfide bridging in peptides using dichloroacetophenone derivatives is developed. This method is highly selective (chemo, diastereo, regio, etc.) and atom economic and works under biocompatible reaction conditions (metal-free, water, pH 7, rt, etc.).
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Affiliation(s)
- Liu-Hai Wu
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
| | - Shuguang Zhou
- Institute of Advanced Synthesis (IAS), Northwestern Polytechnical University (NPU), Xi'an 710072, China.,Yangtze River Delta Research Institute of NPU, Taicang, Jiangsu 215400, China
| | - Qun-Feng Luo
- Institute of Advanced Synthesis (IAS), Northwestern Polytechnical University (NPU), Xi'an 710072, China.,Yangtze River Delta Research Institute of NPU, Taicang, Jiangsu 215400, China
| | - Jie-Sheng Tian
- Institute of Advanced Synthesis (IAS), Northwestern Polytechnical University (NPU), Xi'an 710072, China.,Yangtze River Delta Research Institute of NPU, Taicang, Jiangsu 215400, China.,Institute of Advanced Synthesis (IAS), Nanjing Tech University (NanjingTech), Nanjing 211816, China
| | - Teck-Peng Loh
- Institute of Advanced Synthesis (IAS), Northwestern Polytechnical University (NPU), Xi'an 710072, China.,Yangtze River Delta Research Institute of NPU, Taicang, Jiangsu 215400, China.,Institute of Advanced Synthesis (IAS), Nanjing Tech University (NanjingTech), Nanjing 211816, China.,Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
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21
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Keyghobadi F, Mehdipour M, Nekoukar V, Firouzi J, Kheimeh A, Nobakht Lahrood F, Azimian Zavareh V, Azimi M, Mohammadi M, Sodeifi N, Ebrahimi M. Long-Term Inhibition of Notch in A-375 Melanoma Cells Enhances Tumor Growth Through the Enhancement of AXIN1, CSNK2A3, and CEBPA2 as Intermediate Genes in Wnt and Notch Pathways. Front Oncol 2020; 10:531. [PMID: 32695658 PMCID: PMC7338939 DOI: 10.3389/fonc.2020.00531] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 03/25/2020] [Indexed: 12/14/2022] Open
Abstract
Notch suppression by gamma-secretase inhibitors is a valid approach against melanoma. However, most of studies have evaluated the short-term effect of DAPT on tumor cells or even cancer stem cells. In the present study, we surveyed the short-term and long-term effects of DAPT on the stem cell properties of A375 and NA8 as melanoma cell lines. The effects of DAPT were tested both in vitro and in vivo using xenograft models. In A375 with B-raf mutation, DAPT decreased the level of NOTCH1, NOTH2, and HES1 as downstream genes of the Notch pathway. This was accompanied by enhanced apoptosis after 24 h treatment, arrest in the G2-M phase, and impaired ability of colony and melanosphere formation at the short term. Moreover, tumor growth also reduced during 13 days of treatment. However, long-term treatment of DAPT promoted tumor growth in the xenograft model and enhanced the number and size of colonies and spheroids in vitro. The gene expression studies confirmed the up-regulation of Wnt and Notch downstream genes as well as AXIN1, CSNK2A3, and CEBPA2 following the removal of Notch inhibitor in vitro and in the xenograft model. Moreover, the Gompertz-based mathematical model determined a new drug resistance term in the present study. Our data supported that the long-term and not short-term inhibition of Notch by DAPT may enhance tumor growth and motility through up-regulation of AXIN1, CSNK2A3, and CEBPA2 genes in B-raf mutated A375 cells.
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Affiliation(s)
- Faezeh Keyghobadi
- Department of Developmental Biology, University of Science and Culture, ACECR, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Maryam Mehdipour
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Vahab Nekoukar
- School of Electrical Engineering, Shahid Rajaee Teacher Training University, Tehran, Iran
| | - Javad Firouzi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Abolfazl Kheimeh
- Animal Core Facility, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Tehran, Iran
| | - Fatemeh Nobakht Lahrood
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Vajihe Azimian Zavareh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Masoumeh Azimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Mohammadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Sodeifi
- Department of Pathology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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22
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Yang Y, Li X, Wang T, Guo Q, Xi T, Zheng L. Emerging agents that target signaling pathways in cancer stem cells. J Hematol Oncol 2020; 13:60. [PMID: 32456660 PMCID: PMC7249421 DOI: 10.1186/s13045-020-00901-6] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 05/18/2020] [Indexed: 12/16/2022] Open
Abstract
Cancer stem cells (CSCs) contribute to the initiation, recurrence, and metastasis of cancer; however, there are still no drugs targeting CSCs in clinical application. There are several signaling pathways playing critical roles in CSC progression, such as the Wnt, Hedgehog, Notch, Hippo, and autophagy signaling pathways. Additionally, targeting the ferroptosis signaling pathway was recently shown to specifically kill CSCs. Therefore, targeting these pathways may suppress CSC progression. The structure of small-molecule drugs shows a good spatial dispersion, and its chemical properties determine its good druggability and pharmacokinetic properties. These characteristics make small-molecule drugs show a great advantage in drug development, which is increasingly popular in the market. Thus, in this review, we will summarize the current researches on the small-molecule compounds suppressing CSC progression, including inhibitors of Wnt, Notch, Hedgehog, and autophagy pathways, and activators of Hippo and ferroptosis pathways. These small-molecule compounds emphasize CSC importance in tumor progression and propose a new strategy to treat cancer in clinic via targeting CSCs.
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Affiliation(s)
- Yue Yang
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Ting Wang
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450003, People's Republic of China
| | - Tao Xi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
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Kojima K, Yakushiji F, Katsuyama A, Ichikawa S. Total Synthesis of Echinomycin and Its Analogues. Org Lett 2020; 22:4217-4221. [DOI: 10.1021/acs.orglett.0c01268] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Keita Kojima
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Fumika Yakushiji
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
- Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Akira Katsuyama
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
- Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Satoshi Ichikawa
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
- Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
- Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6,
Kita-ku, Sapporo 060-0812, Sapporo, Japan
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24
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Koike K, Nagano M, Ebihara M, Hirayama T, Tsuji M, Suga H, Nagasawa H. Design, Synthesis, and Conformation-Activity Study of Unnatural Bridged Bicyclic Depsipeptides as Highly Potent Hypoxia Inducible Factor-1 Inhibitors and Antitumor Agents. J Med Chem 2020; 63:4022-4046. [PMID: 32202785 DOI: 10.1021/acs.jmedchem.9b02039] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
By carrying out structural modifications based on the bicyclic peptide structure of echinomycin, we successfully synthesized various powerful antitumor derivatives. The ring conformation in the obtained compounds was restricted by cross-linking with an unnatural bond. The prepared derivatives were demonstrated to strongly suppress the hypoxia inducible factor (HIF)-1 transcriptional activation and hypoxia induction of HIF-1 protein expression. Particularly, alkene-bridged derivative 12 exhibited remarkably potent cytotoxicity (IC50 = 0.22 nM on the MCF-7 cell line) and HIF-1 inhibition (IC50 = 0.09 nM), which considerably exceeded those of echinomycin. Conformational analyses and molecular modeling studies revealed that the biological activities were enhanced following restriction of the conformation by cross-linking through a metabolically stable and rigid bridge bond. In addition, we proposed a new globular conformation stabilized by intramolecular π stacking that can contribute to the biological effects of bicyclic depsipeptides. The developments presented in the current study serve as a useful guide to expand the chemical space of peptides in drug discovery.
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Affiliation(s)
- Kota Koike
- Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu-city, Gifu 501-1196, Japan
| | - Masanobu Nagano
- Department of Chemistry, The University of Tokyo, Bunkyoku, Tokyo 113-0033, Japan
| | - Masahiro Ebihara
- Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu-city, Gifu 501-1193, Japan
| | - Tasuku Hirayama
- Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu-city, Gifu 501-1196, Japan
| | - Mieko Tsuji
- Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu-city, Gifu 501-1196, Japan
| | - Hiroaki Suga
- Department of Chemistry, The University of Tokyo, Bunkyoku, Tokyo 113-0033, Japan
| | - Hideko Nagasawa
- Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu-city, Gifu 501-1196, Japan
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25
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Steinbichler TB, Savic D, Dudás J, Kvitsaridze I, Skvortsov S, Riechelmann H, Skvortsova II. Cancer stem cells and their unique role in metastatic spread. Semin Cancer Biol 2020; 60:148-156. [PMID: 31521746 DOI: 10.1016/j.semcancer.2019.09.007] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/10/2019] [Accepted: 09/11/2019] [Indexed: 12/19/2022]
Abstract
Cancer stem cells (CSC) possess abilities generally associated with embryonic or adult stem cells, especially self-renewal and differentiation, but also dormancy and cellular plasticity that allow adaption to new environmental circumstances. These abilities are ideal prerequisites for the successful establishment of metastasis. This review highlights the role of CSCs in every step of the metastatic cascade from cancer cell invasion into blood vessels, survival in the blood stream, attachment and extravasation as well as colonization of the host organ and subsequent establishment of distant macrometastasis.
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Affiliation(s)
| | - Dragana Savic
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - József Dudás
- Department of Otorhinolaryngology, Medical University of Innsbruck, Innsbruck, Austria
| | - Irma Kvitsaridze
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - Sergej Skvortsov
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - Herbert Riechelmann
- Department of Otorhinolaryngology, Medical University of Innsbruck, Innsbruck, Austria
| | - Ira-Ida Skvortsova
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria.
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26
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Dandawate P, Ghosh C, Palaniyandi K, Paul S, Rawal S, Pradhan R, Sayed AAA, Choudhury S, Standing D, Subramaniam D, Padhye S, Gunewardena S, Thomas SM, O’ Neil M, Tawfik O, Welch DR, Jensen RA, Maliski S, Weir S, Iwakuma T, Anant S, Dhar A. The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 and Promotes Tumorigenesis in Mice. Gastroenterology 2019; 157:1646-1659.e11. [PMID: 31442435 PMCID: PMC6878178 DOI: 10.1053/j.gastro.2019.08.018] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 07/31/2019] [Accepted: 08/08/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The histone lysine demethylase 3A (KDM3A) demethylates H3K9me1 and H3K9Me2 to increase gene transcription and is upregulated in tumors, including pancreatic tumors. We investigated its activities in pancreatic cancer cell lines and its regulation of the gene encoding doublecortin calmodulin-like kinase 1 (DCLK1), a marker of cancer stem cells. METHODS We knocked down KDM3A in MiaPaCa-2 and S2-007 pancreatic cancer cell lines and overexpressed KDM3A in HPNE cells (human noncancerous pancreatic ductal cell line); we evaluated cell migration, invasion, and spheroid formation under hypoxic and normoxic conditions. Nude mice were given orthotopic injections of S2-007 cells, with or without (control) knockdown of KDM3A, and HPNE cells, with or without (control) overexpression of KDM3A; tumor growth was assessed. We analyzed pancreatic tumor tissues from mice and pancreatic cancer cell lines by immunohistochemistry and immunoblotting. We performed RNA-sequencing analysis of MiaPaCa-2 and S2-007 cells with knockdown of KDM3A and evaluated localization of DCLK1 and KDM3A by immunofluorescence. We analyzed the cancer genome atlas for levels of KDM3A and DCLK1 messenger RNA in human pancreatic ductal adenocarcinoma (PDAC) tissues and association with patient survival time. RESULTS Levels of KDM3A were increased in human pancreatic tumor tissues and cell lines, compared with adjacent nontumor pancreatic tissues, such as islet and acinar cells. Knockdown of KDM3A in S2-007 cells significantly reduced colony formation, invasion, migration, and spheroid formation, compared with control cells, and slowed growth of orthotopic tumors in mice. We identified KDM3A-binding sites in the DCLK1 promoter; S2-007 cells with knockdown of KDM3A had reduced levels of DCLK1. HPNE cells that overexpressed KDM3A formed foci and spheres in culture and formed tumors and metastases in mice, whereas control HPNE cells did not. Hypoxia induced sphere formation and increased levels of KDM3A in S2-007 cells and in HPNE cells that overexpressed DCLK1, but not control HPNE cells. Levels of KDM3A and DCLK1 messenger RNA were higher in human PDAC than nontumor pancreatic tissues and correlated with shorter survival times of patients. CONCLUSIONS We found human PDAC samples and pancreatic cancer cell lines to overexpress KDM3A. KDM3A increases expression of DCLK1, and levels of both proteins are increased in human PDAC samples. Knockdown of KDM3A in pancreatic cancer cell lines reduced their invasive and sphere-forming activities in culture and formation of orthotopic tumors in mice. Hypoxia increased expression of KDM3A in pancreatic cancer cells. Strategies to disrupt this pathway might be developed for treatment of pancreatic cancer.
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Affiliation(s)
- Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Chandrayee Ghosh
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Kanagaraj Palaniyandi
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Santanu Paul
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Sonia Rawal
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Rohan Pradhan
- Interdisciplinary Science and Technology Research Academy, Abeda Inamdar Senior College, Camp, Pune 411001, India
| | - Afreen Asif Ali Sayed
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Sonali Choudhury
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - David Standing
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Dharmalingam Subramaniam
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Subhash Padhye
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.,Interdisciplinary Science and Technology Research Academy, Abeda Inamdar Senior College, Camp, Pune 411001, India
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Sufi M. Thomas
- Department of Otolaryngology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Moura O’ Neil
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Ossama Tawfik
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Danny R. Welch
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Roy A. Jensen
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Sally Maliski
- School of Nursing, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Scott Weir
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Tomoo Iwakuma
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas.
| | - Animesh Dhar
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas.
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27
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Krishnamachary B, Subramaniam D, Dandawate P, Ponnurangam S, Srinivasan P, Ramamoorthy P, Umar S, Thomas SM, Dhar A, Septer S, Weir SJ, Attard T, Anant S. Targeting transcription factor TCF4 by γ-Mangostin, a natural xanthone. Oncotarget 2019; 10:5576-5591. [PMID: 31608135 PMCID: PMC6771460 DOI: 10.18632/oncotarget.27159] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 07/17/2019] [Indexed: 01/29/2023] Open
Abstract
Given that colon cancer is the third most common cancer in incidence and cause of death in the United States, and current treatment modalities are insufficient, there is a need to develop novel agents. Towards this, here we focus on γ-Mangostin, a bioactive compound present in the Mangosteen (Garcinia mangostana) fruit. γ-Mangostin suppressed proliferation and colony formation, and induced cell cycle arrest and apoptosis of colon cancer cell lines. Further, γ-Mangostin inhibited colonosphere formation. Molecular docking and CETSA (Cellular thermal shift assay) binding assays demonstrated that γ-Mangostin interacts with transcription factor TCF4 (T-Cell Factor 4) at the β-catenin binding domain with the binding energy of -5.5 Kcal/mol. Moreover, γ-Mangostin treatment decreased TCF4 expression and reduced TCF reporter activity. The compound also suppressed the expression of Wnt signaling target proteins cyclin D1 and c-Myc, and stem cell markers such as LGR5, DCLK1 and CD44. To determine the effect of γ-Mangostin on tumor growth in vivo, we administered nude mice harboring HCT116 tumor xenografts with 5 mg/Kg of γ-Mangostin intraperitoneally for 21 days. γ-Mangostin treatment significantly suppressed tumor growth, with notably lowered tumor volume and weight. In addition, western blot analysis revealed a significant decrease in the expression of TCF4 and its downstream targets such as cyclin D1 and c-Myc. Together, these data suggest that γ-Mangostin inhibits colon cancer growth through targeting TCF4. γ-Mangostin may be a potential therapeutic agent for colon cancer.
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Affiliation(s)
- Balaji Krishnamachary
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | | | - Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Sivapriya Ponnurangam
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | | | - Prabhu Ramamoorthy
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Shahid Umar
- Department of General Surgery, University of Kansas Medical Center, Kansas City, KS, USA
| | - Sufi Mary Thomas
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Animesh Dhar
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Seth Septer
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Colorado, Aurora, CO, USA
| | - Scott J Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Thomas Attard
- Department of Pediatrics, Division of Gastroenterology, Children's Mercy Hospital, Kansas City, KS, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
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Ding X, Li F, Zhang L. Knockdown of Delta-like 3 restricts lipopolysaccharide-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated epithelial-mesenchymal transition. Life Sci 2019; 226:149-155. [PMID: 30981764 DOI: 10.1016/j.lfs.2019.04.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 04/07/2019] [Accepted: 04/10/2019] [Indexed: 12/11/2022]
Abstract
AIMS To investigate the effects and mechanisms of DLL3 in inflammation-mediated A2058 melanoma cell invasion and metastasis. MATERIALS AND METHODS Melanoma A2058 cells was stimulated with lipopolysaccharide (LPS), with or without transfection of DLL3 siRNA, or DLL3 overexpression vector, or Twist1 siRNA. Cell migration and invasion were detected by wound healing and transwell invasion assay. The production of inflammatory factors TNF-α and IL-6 was measured by ELISA. The expression of Notch signaling-related molecules was detected by PCR and western blot. The protein expression of MMP1, MMP9, VEGF, DLL3, and EMT-related molecules was tested by western blot. KEY FINDINGS LPS treatment increased migration and invasion of A2058 cells, accompanied by increased expression of TNF-α and IL-6. DLL3 was both upregulated in the LPS- or TNF-α-stimulated A2058 cells, and DLL3 knockdown inhibited LPS-induced inflammation, migration and invasion of A2058 cells, accompanied by down-regulation of MMP1, MMP9 and VEGF. Besides, DLL3 knockdown inhibits the expression of Twist1, a key EMT regulating factor, as well as the EMT hallmarks slug, N-cadherin and vimentin. Moreover, Twist1 silence inhibited EMT, and limited LPS-induced migration and invasion of A2058 cells, with decreased expression of MMP1, MMP9 and VEGF and reduced production of TNF-α and IL-6 in LPS-stimulated A2058 cells. SIGNIFICANCE Knockdown of DLL3 restricts LPS-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated EMT. Therefore, targeting DLL3 may be a promising therapeutic strategy against inflammation-aggravated melanoma progression.
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Affiliation(s)
- Xiaojie Ding
- Department of Dermatology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan, China
| | - Fuyao Li
- Department of Oncology Radiotherapy, Cancer Center, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, Zhejiang, China
| | - Li Zhang
- Department of Dermatology, The First People's Hospital of Lanzhou City, Lanzhou 730050, Gansu, China.
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29
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Super-enhancers: novel target for pancreatic ductal adenocarcinoma. Oncotarget 2019; 10:1554-1571. [PMID: 30899425 PMCID: PMC6422180 DOI: 10.18632/oncotarget.26704] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 02/01/2019] [Indexed: 01/02/2023] Open
Abstract
Super-enhancers (SEs) are unique areas of the genome which drive high-level of transcription and play a pivotal role in the cell physiology. Previous studies have established several important genes in cancer as SE-driven oncogenes. It is likely that oncogenes may hack the resident tissue regenerative program and interfere with SE-driven repair networks, leading to the specific pancreatic ductal adenocarcinoma (PDAC) phenotype. Here, we used ChIP-Seq to identify the presence of SE in PDAC cell lines. Differential H3K27AC marks were identified at enhancer regions of genes including c-MYC, MED1, OCT-4, NANOG, and SOX2 that can act as SE in non-cancerous, cancerous and metastatic PDAC cell lines. GZ17-6.02 affects acetylation of the genes, reduces transcription of major transcription factors, sonic hedgehog pathway proteins, and stem cell markers. In accordance with the decrease in Oct-4 expression, ChIP-Seq revealed a significant decrease in the occupancy of OCT-4 in the entire genome after GZ17-6.02 treatment suggesting the possible inhibitory effect of GZ17-6.02 on PDAC. Hence, SE genes are associated with PDAC and targeting their regulation with GZ17-6.02 offers a novel approach for treatment.
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30
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Di Carlo C, Brandi J, Cecconi D. Pancreatic cancer stem cells: Perspectives on potential therapeutic approaches of pancreatic ductal adenocarcinoma. World J Stem Cells 2018; 10:172-182. [PMID: 30631392 PMCID: PMC6325076 DOI: 10.4252/wjsc.v10.i11.172] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/10/2018] [Accepted: 10/17/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive solid tumours of the pancreas, characterised by a five-year survival rate less than 8%. Recent reports that pancreatic cancer stem cells (PCSCs) contribute to the tumorigenesis, progression, and chemoresistance of pancreatic cancer have prompted the investigation of new therapeutic approaches able to directly target PCSCs. In the present paper the non-cancer related drugs that have been proposed to target CSCs that could potentially combat pancreatic cancer are reviewed and evaluated. The role of some pathways and deregulated proteins in PCSCs as new therapeutic targets are also discussed with a focus on selected specific inhibitors. Finally, advances in the development of nanoparticles for targeting PCSCs and site-specific drug delivery are highlighted, and their limitations considered.
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Affiliation(s)
- Claudia Di Carlo
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
| | - Jessica Brandi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy.
| | - Daniela Cecconi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
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31
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Han F, Xu Q, Zhao J, Xiong P, Liu J. ERO1L promotes pancreatic cancer cell progression through activating the Wnt/catenin pathway. J Cell Biochem 2018; 119:8996-9005. [PMID: 30076651 DOI: 10.1002/jcb.27155] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 05/18/2018] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer is a lethal malignancy with an extremely poor prognosis. Although many genes and noncoding RNAs have been found to regulate its progression, more regulators are needed to be understood to resolve its high lethality. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) plays crucial roles in the progression of various tumors, but its role in pancreatic cancer progression has not been studied. In this study, we found that ERO1L was significantly upregulated in pancreatic cancer cells and patients; its overexpression significantly promoted pancreatic cancer migration, invasion, and growth, while its knockdown significantly inhibited pancreatic cancer migration, invasion, and growth. Mechanism analysis suggested that ERO1L promoted many tumor-associated signaling pathways, especially the Wnt/catenin pathway; it could activate the Wnt/catenin pathway and upregulate the targets of the Wnt/catenin pathway. We further analyzed the correlation between ERO1L expression and the prognosis of patients, suggesting that patients with high ERO1L expression had short survival time; it is an independent prognosis factor for patients' prognosis. Together, we found that ERO1L was an oncogene for pancreatic cancer.
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Affiliation(s)
- Fei Han
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qianqian Xu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jianguo Zhao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Peng Xiong
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jun Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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32
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Subramaniam D, Kaushik G, Dandawate P, Anant S. Targeting Cancer Stem Cells for Chemoprevention of Pancreatic Cancer. Curr Med Chem 2018; 25:2585-2594. [PMID: 28137215 DOI: 10.2174/0929867324666170127095832] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 12/17/2016] [Accepted: 12/17/2016] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma is one of the deadliest cancers worldwide and the fourth leading cause of cancer-related deaths in United States. Regardless of the advances in molecular pathogenesis and consequential efforts to suppress the disease, this cancer remains a major health problem in United States. By 2030, the projection is that pancreatic cancer will be climb up to be the second leading cause of cancer-related deaths in the United States. Pancreatic cancer is a rapidly invasive and highly metastatic cancer, and does not respond to standard therapies. Emerging evidence supports that the presence of a unique population of cells called cancer stem cells (CSCs) as potential cancer inducing cells and efforts are underway to develop therapeutic strategies targeting these cells. CSCs are rare quiescent cells, and with the capacity to self-renew through asymmetric/symmetric cell division, as well as differentiate into various lineages of cells in the cancer. Studies have been shown that CSCs are highly resistant to standard therapy and also responsible for drug resistance, cancer recurrence and metastasis. To overcome this problem, we need novel preventive agents that target these CSCs. Natural compounds or phytochemicals have ability to target these CSCs and their signaling pathways. Therefore, in the present review article, we summarize our current understanding of pancreatic CSCs and their signaling pathways, and the phytochemicals that target these cells including curcumin, resveratrol, tea polyphenol EGCG (epigallocatechin- 3-gallate), crocetinic acid, sulforaphane, genistein, indole-3-carbinol, vitamin E δ- tocotrienol, Plumbagin, quercetin, triptolide, Licofelene and Quinomycin. These natural compounds or phytochemicals, which inhibit cancer stem cells may prove to be promising agents for the prevention and treatment of pancreatic cancers.
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Affiliation(s)
- Dharmalingam Subramaniam
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States.,The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Gaurav Kaushik
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Prasad Dandawate
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Shrikant Anant
- Department of Surgery, the University of Kansas Medical Center, Kansas City, KS 66160, United States.,The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, United States
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33
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Harbuzariu A, Oprea-Ilies GM, Gonzalez-Perez RR. The Role of Notch Signaling and Leptin-Notch Crosstalk in Pancreatic Cancer. MEDICINES (BASEL, SWITZERLAND) 2018; 5:medicines5030068. [PMID: 30004402 PMCID: PMC6164868 DOI: 10.3390/medicines5030068] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 06/27/2018] [Accepted: 06/29/2018] [Indexed: 02/06/2023]
Abstract
There is accumulating evidence that deregulated Notch signaling affects cancer development, and specifically pancreatic cancer (PC) progression. Notch canonical and non-canonical signaling has diverse impact on PC. Moreover, the actions of RBP-Jk (nuclear partner of activated Notch) independent of Notch signaling pathway seem to affect differently cancer progression. Recent data show that in PC and other cancer types the adipokine leptin can modulate Notch/RBP-Jk signaling, thereby, linking the pandemic obesity with cancer and chemoresistance. The potential pivotal role of leptin on PC, and its connection with Notch signaling and chemoresistance are still not completely understood. In this review, we will describe the most important aspects of Notch-RBP-Jk signaling in PC. Further, we will discuss on studies related to RBP-Jk-independent Notch and Notch-independent RPB-Jk signaling. We will also discuss on the novel crosstalk between leptin and Notch in PC and its implications in chemoresistance. The effects of leptin-Notch/RBP-Jk signaling on cancer cell proliferation, apoptosis, and drug resistance require more investigation. Data from these investigations could help to open unexplored ways to improve PC treatment success that has shown little progress for many years.
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Affiliation(s)
- Adriana Harbuzariu
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA.
| | | | - Ruben R Gonzalez-Perez
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA.
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34
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Asnaghi L, Tripathy A, Yang Q, Kaur H, Hanaford A, Yu W, Eberhart CG. Targeting Notch signaling as a novel therapy for retinoblastoma. Oncotarget 2018; 7:70028-70044. [PMID: 27661116 PMCID: PMC5342532 DOI: 10.18632/oncotarget.12142] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Accepted: 09/14/2016] [Indexed: 01/15/2023] Open
Abstract
Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied the role of Notch signaling in promoting retinoblastoma proliferation. Moderate or strong nuclear expression of Hes1 was found in 10 of 11 human retinoblastoma samples analyzed immunohistochemically, supporting a role for Notch in retinoblastoma growth. Notch pathway components were present in WERI Rb1 and Y79 retinoblastoma lines, with Jag2 and DLL4 more highly expressed than other ligands, and Notch1 and Notch2 more abundant than Notch3. The cleaved/active form of Notch1 was detectable in both lines. Inhibition of the pathway, achieved using a γ-secretase inhibitor (GSI) or by downregulating Jag2, DLL4 or CBF1 using short hairpin RNA, potently reduced growth, proliferation and clonogenicity in both lines. Upregulation of CXCR4 and CXCR7 and downregulation of PI3KC2β were identified by microarray upon Jag2 suppression. The functional importance of PI3KC2β was confirmed using shRNA. Synergy was found by combining GSI with Melphalan at their IC50. These findings indicate that Notch pathway is active in WERI Rb1 and Y79, and in most human retinoblastoma samples, and suggest that Notch antagonists may represent a new approach to more effectively treat retinoblastoma.
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Affiliation(s)
- Laura Asnaghi
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Arushi Tripathy
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Qian Yang
- Department of Ophthalmology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Harpreet Kaur
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Allison Hanaford
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Wayne Yu
- Microarray Core Facility, Sidney Kimmel Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Charles G Eberhart
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.,Department of Ophthalmology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.,Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
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35
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Paschall AV, Yang D, Lu C, Redd PS, Choi JH, Heaton CM, Lee JR, Nayak-Kapoor A, Liu K. CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype. Oncotarget 2018; 7:78698-78712. [PMID: 27659530 PMCID: PMC5346671 DOI: 10.18632/oncotarget.12168] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 09/12/2016] [Indexed: 12/13/2022] Open
Abstract
The chemotherapeutic agent 5-Fluorouracil (5-FU) is the most commonly used drug for patients with advanced colon cancer. However, development of resistance to 5-FU is inevitable in almost all patients. The mechanism by which colon cancer develops 5-FU resistance is still unclear. One recently proposed theory is that cancer stem-like cells underlie colon cancer 5-FU resistance, but the phenotypes of 5-FU-resistant colon cancer stem cells are still controversial. We report here that 5-FU treatment selectively enriches a subset of CD133+ colon cancer cells in vitro. 5-FU chemotherapy also increases CD133+ tumor cells in human colon cancer patients. However, sorted CD133+ colon cancer cells exhibit no increased resistance to 5-FU, and CD133 levels exhibit no correlation with colon cancer patient survival or cancer recurrence. Genome-wide analysis of gene expression between sorted CD133+ colon cancer cells and 5-FU-selected colon cancer cells identifies 207 differentially expressed genes. CD24 is one of the genes whose expression level is lower in the CD133+ and 5-FU-resistant colon cancer cells as compared to CD133+ and 5-FU-sensitive colon cancer cells. Consequently, CD133+CD24lo cells exhibit decreased sensitivity to 5-FU. Therefore, we determine that CD133+CD24lo phenotype defines 5-FU-resistant human colon cancer stem cell-like cells.
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Affiliation(s)
- Amy V Paschall
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.,Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.,Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Dafeng Yang
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.,Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Chunwan Lu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.,Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Priscilla S Redd
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.,Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.,Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Jeong-Hyeon Choi
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
| | | | - Jeffrey R Lee
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Asha Nayak-Kapoor
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.,Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.,Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.,Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
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36
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Zhang Y, Yang C, Cheng H, Fan Z, Huang Q, Lu Y, Fan K, Luo G, Jin K, Wang Z, Liu C, Yu X. Novel agents for pancreatic ductal adenocarcinoma: emerging therapeutics and future directions. J Hematol Oncol 2018; 11:14. [PMID: 29386069 PMCID: PMC5793409 DOI: 10.1186/s13045-017-0551-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 12/28/2017] [Indexed: 02/08/2023] Open
Abstract
A poor prognosis of pancreatic ductal adenocarcinoma (PDAC) associated with chemoresistance has not changed for the past three decades. A multidisciplinary diagnosis followed by surgery and chemo(radiation)therapy is the main treatment approach. However, gemcitabine- and 5-fluorouracil-based therapies did not present satisfying outcomes. Novel regimens targeting pancreatic cancer cells, the tumor microenvironment, and immunosuppression are emerging. Biomarkers concerning the treatment outcome and patient selection are being discovered in preclinical or clinical studies. Combination therapies of classic chemotherapeutic drugs and novel agents or novel therapeutic combinations might bring hope to the dismal prognosis for PDAC patients.
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Affiliation(s)
- Yiyin Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Chao Yang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - He Cheng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Zhiyao Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Qiuyi Huang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Yu Lu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Kun Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Guopei Luo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Zhengshi Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Chen Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
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McCubrey JA, Abrams SL, Lertpiriyapong K, Cocco L, Ratti S, Martelli AM, Candido S, Libra M, Murata RM, Rosalen PL, Lombardi P, Montalto G, Cervello M, Gizak A, Rakus D, Steelman LS. Effects of berberine, curcumin, resveratrol alone and in combination with chemotherapeutic drugs and signal transduction inhibitors on cancer cells-Power of nutraceuticals. Adv Biol Regul 2018; 67:190-211. [PMID: 28988970 DOI: 10.1016/j.jbior.2017.09.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 09/29/2017] [Indexed: 06/07/2023]
Abstract
Over the past fifty years, society has become aware of the importance of a healthy diet in terms of human fitness and longevity. More recently, the concept of the beneficial effects of certain components of our diet and other compounds, that are consumed often by different cultures in various parts of the world, has become apparent. These "healthy" components of our diet are often referred to as nutraceuticals and they can prevent/suppress: aging, bacterial, fungal and viral infections, diabetes, inflammation, metabolic disorders and cardiovascular diseases and have other health-enhancing effects. Moreover, they are now often being investigated because of their anti-cancer properties/potentials. Understanding the effects of various natural products on cancer cells may enhance their usage as anti-proliferative agents which may be beneficial for many health problems. In this manuscript, we discuss and demonstrate how certain nutraceuticals may enhance other anti-cancer drugs to suppress proliferation of cancer cells.
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Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
| | - Stephen L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine at East Carolina University, USA; Center of Comparative Medicine and Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine and the Hospital for Special Surgery, New York City, New York, USA
| | - Lucio Cocco
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Stefano Ratti
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Alberto M Martelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences - Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences - Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Ramiro M Murata
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA; Department of Foundational Sciences, School of Dental Medicine, East Carolina University, USA
| | - Pedro L Rosalen
- Department of Physiological Sciences, Piracicaba Dental School, State University of Campinas, Piracicaba, Brazil
| | - Paolo Lombardi
- Naxospharma, Via Giuseppe Di Vittorio 70, Novate Milanese 20026, Italy
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy; Consiglio Nazionale Delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Melchiorre Cervello
- Consiglio Nazionale Delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Agnieszka Gizak
- Department of Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | - Dariusz Rakus
- Department of Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
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38
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Wang Z, Zhao K, Hackert T, Zöller M. CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression. Front Cell Dev Biol 2018; 6:97. [PMID: 30211160 PMCID: PMC6122270 DOI: 10.3389/fcell.2018.00097] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 08/08/2018] [Indexed: 12/19/2022] Open
Abstract
Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker. Knockdown and knockout models accompanied by loss of tumor progression despite unaltered primary tumor growth unraveled that these markers are indispensable for CIC. The unexpected contribution of marker molecules to CIC-related activities prompted research on underlying molecular mechanisms. This review outlines the contribution of CD44, particularly CD44v6 to CIC activities. A first focus is given to the impact of CD44/CD44v6 to inherent CIC features, including the crosstalk with the niche, apoptosis-resistance, and epithelial mesenchymal transition. Following the steps of the metastatic cascade, we report on supporting activities of CD44/CD44v6 in migration and invasion. These CD44/CD44v6 activities rely on the association with membrane-integrated and cytosolic signaling molecules and proteases and transcriptional regulation. They are not restricted to, but most pronounced in CIC and are tightly regulated by feedback loops. Finally, we discuss on the engagement of CD44/CD44v6 in exosome biogenesis, loading and delivery. exosomes being the main acteurs in the long-distance crosstalk of CIC with the host. In brief, by supporting the communication with the niche and promoting apoptosis resistance CD44/CD44v6 plays an important role in CIC maintenance. The multifaceted interplay between CD44/CD44v6, signal transducing molecules and proteases facilitates the metastasizing tumor cell journey through the body. By its engagement in exosome biogenesis CD44/CD44v6 contributes to disseminated tumor cell settlement and growth in distant organs. Thus, CD44/CD44v6 likely is the most central CIC biomarker.
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Affiliation(s)
- Zhe Wang
- Department of Oncology, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong, China
| | - Kun Zhao
- Pancreas Section, University Hospital of Surgery, Heidelberg, Germany
| | - Thilo Hackert
- Pancreas Section, University Hospital of Surgery, Heidelberg, Germany
| | - Margot Zöller
- Pancreas Section, University Hospital of Surgery, Heidelberg, Germany
- *Correspondence: Margot Zöller
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39
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Di Martile M, Desideri M, De Luca T, Gabellini C, Buglioni S, Eramo A, Sette G, Milella M, Rotili D, Mai A, Carradori S, Secci D, De Maria R, Del Bufalo D, Trisciuoglio D. Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells. Oncotarget 2017; 7:11332-48. [PMID: 26870991 PMCID: PMC4905477 DOI: 10.18632/oncotarget.7238] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 01/23/2016] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC.
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Affiliation(s)
- Marta Di Martile
- Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
| | - Marianna Desideri
- Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
| | - Teresa De Luca
- Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
| | - Chiara Gabellini
- Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
| | - Simonetta Buglioni
- Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
| | - Adriana Eramo
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Giovanni Sette
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Michele Milella
- Clinical and Experimental Oncology Department, Regina Elena National Cancer Institute, Rome, Italy
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, 'Sapienza' University, Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, 'Sapienza' University, Rome, Italy.,Pasteur Institute, Cenci Bolognetti Foundation, 'Sapienza' University, Rome, Italy
| | - Simone Carradori
- Department of Drug Chemistry and Technologies, 'Sapienza' University, Rome, Italy
| | - Daniela Secci
- Department of Drug Chemistry and Technologies, 'Sapienza' University, Rome, Italy
| | - Ruggero De Maria
- Scientific Director, Regina Elena National Cancer Institute, Rome, Italy
| | - Donatella Del Bufalo
- Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
| | - Daniela Trisciuoglio
- Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
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Wang HH, Liao CC, Chow NH, Huang LLH, Chuang JI, Wei KC, Shin JW. Whether CD44 is an applicable marker for glioma stem cells. Am J Transl Res 2017; 9:4785-4806. [PMID: 29218080 PMCID: PMC5714766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 06/16/2017] [Indexed: 06/07/2023]
Abstract
Glioblastoma multiforme (GBM) is one of the most malignant and aggressive brain tumors with great amount of hyaluronan (HA) secretion and CD44 overexpression (HA receptor). CD44 has been suggested as a cancer stem cells (CSCs) marker. However, several clinical studies have indicated that CD44low glioma cell exhibit CSCs traits. Additionally, our previous study indicated that more CD44 expression was associated with a better prognosis in GBM patients. To determine whether CD44 is an appropriate marker of glioma stem cells (GSCs), we manipulated CD44 expression using intrinsic (CD44 knockdown, CD44kd) and extrinsic (HA supplement, HA+) methods. Our results show that CD44kd suppressed cell proliferation by retarding cell cycle progression from G0/G1 to S phase. Furthermore, it caused GSCs traits, including lower expression of differentiation marker (glial fibrillary acidic protein, GFAP), a higher level of sphere formation and higher expression of stem cell markers (CD133, nestin and Oct4). The reduction of CD44 expression induced by HA+ was accompanied by an increase in GSCs properties. Interestingly, the presence of HA+ in glioma cells with GSC traits conversely facilitated differentiation. Our data indicated that the CD44 low-expressing cells exhibit more GSCs straits, suggesting that CD44 is not an appropriate marker for GSCs. Furthermore, the preferential expression of CD44 at the invasive rim in rat glioma specimen implies that CD44 may be more important for invasion and migration instead of GSCs marker in glioma.
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Affiliation(s)
- Hsiao-Han Wang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
| | - Chen-Chieh Liao
- Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung UniversityTainan, Taiwan
| | - Nan-Haw Chow
- Department of Pathology, National Cheng Kung University HospitalTainan, Taiwan
- Graduate Institute of Molecular Medicine, National Cheng Kung University College of MedicineTainan, Taiwan
| | - Lynn Ling-Huei Huang
- Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung UniversityTainan, Taiwan
- Institute of Clinical Medicine, National Cheng Kung UniversityTainan, Taiwan
| | - Jih-Ing Chuang
- Department of Physiology, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
| | - Kuo-Chen Wei
- Department of Neurosurgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan
| | - Jyh-Wei Shin
- Department of Parasitology, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
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Dai JJ, Jiang MJ, Wang XP, Tian L. Inflammation-Related Pancreatic Carcinogenesis: Mechanisms and Clinical Potentials in Advances. Pancreas 2017; 46:973-985. [PMID: 28796135 DOI: 10.1097/mpa.0000000000000886] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Chronic inflammation has long been considered critical in pancreatic carcinogenesis, and recently studies showed that some anti-inflammatory agents such as aspirin could potentially be used to attenuate pancreatic carcinogenesis. Several inflammation-related critical transcription factors and pathways such as NF-κB (nuclear factor κ-light-chain enhancer of activated B cells) and reactive oxygen species have been confirmed to be involved in carcinogenesis. However, its underlying mechanisms are far from clear, which largely limits further development of potential anticarcinogenesis drugs. As a result, it is of great importance for us to better understand and gain a better perspective in inflammation-related pancreatic carcinogenesis. In this review, we systematically analyzed recent advances concerning inflammation-related pancreatic carcinogenesis and brought out the possible underlying mechanisms. Potential preventive and therapeutic strategies based on anti-inflammatory agents have also been further discussed.
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Affiliation(s)
- Juan-Juan Dai
- From the *Shanghai Key Laboratory of Pancreatic Diseases, †Institute of Translational Medicine, and ‡Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Deng G, Zheng X, Jiang P, Chen K, Wang X, Jiang K, Zhang W, Tu L, Yan D, Ma L, Ma S. Notch1 suppresses prostate cancer cell invasion via the metastasis-associated 1-KiSS-1 metastasis-suppressor pathway. Oncol Lett 2017; 14:4477-4482. [PMID: 29085444 PMCID: PMC5649609 DOI: 10.3892/ol.2017.6761] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 02/14/2017] [Indexed: 01/28/2023] Open
Abstract
Notch1 is a type-1 transmembrane receptor which has been demonstrated to be involved in proliferation in various organisms. A number of studies have proposed that Notch signaling may be aberrantly activated, thus contributing to development, invasion and metastasis in a variety of human cancers. In the present study, the function and mechanism of Notch1 in human prostate cancer (PCa) LNCaP cells in vitro was investigated. Notch1 and cleaved-Notch1 expression were evaluated in human PCa cell lines, including LNCaP, PC-3 and DU 145, and the human prostate epithelial RWPE-1 cell line. LNCaP cells were transfected with Notch1-targeting short hairpin RNAs (shRNAs) and the level of proliferation, the ability to invade and the expression of genes associated with cancer cell invasion were subsequently investigated. Notch1 was highly expressed in LNCaP, PC-3 and DU 145 cells compared with RWPE-1 cells, while cleaved-Notch1 was expressed in LNCaP, PC-3 and DU 145 cells, and only to a minimal extent in RWPE-1 cells. Knockdown of Notch1 by shRNA in LNCaP cells markedly decreased cell invasion through Matrigel and inhibited cell proliferation 48 h following transfection. Reverse transcription-quantitative polymerase chain reaction analysis indicated that Notch1-knockdown resulted in a significant reduction of metastasis-associated 1 (MTA1) and increase of KiSS-1 metastasis-suppressor (KISS-1), mitogen-activated protein kinase 4 (MKK4) and cluster of differentiation 82 (KAI1). The present data demonstrated that expression of Notch1 was significantly associated with the invasion of prostate cancer. Knockdown of Notch1 decreased the invasive ability of LNCaP cells, which may be caused by downregulating MTA1 and upregulating KISS-1, MKK4 and KAI1. These findings indicated that targeting Notch1 may provide a novel method of suppressing or treating metastasis in prostate cancer.
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Affiliation(s)
- Gang Deng
- Department of Urology, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiaoliang Zheng
- Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310000, P.R. China
| | - Peiwu Jiang
- Zhejiang Chinese Medical University and Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China
| | - Kean Chen
- Zhejiang Chinese Medical University and Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiaoju Wang
- Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310000, P.R. China
| | - Kang Jiang
- Department of Urology, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China
| | - Wenjun Zhang
- Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310000, P.R. China
| | - Linglan Tu
- Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310000, P.R. China
| | - Dongmei Yan
- Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310000, P.R. China
| | - Libin Ma
- Department of Nephrology, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China
| | - Shenglin Ma
- Department of Oncology, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China
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Repurposing Established Compounds to Target Pancreatic Cancer Stem Cells (CSCs). Med Sci (Basel) 2017; 5:medsci5020014. [PMID: 29099030 PMCID: PMC5635789 DOI: 10.3390/medsci5020014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/11/2017] [Accepted: 06/11/2017] [Indexed: 02/08/2023] Open
Abstract
The diagnosis of pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, in particular, when patients present with unresectable disease. While significant progress has been made in understanding the biology of PDAC, this knowledge has not translated into a clear clinical benefit and current chemotherapeutic strategies only offer a modest improvement in overall survival. Accordingly, novel approaches are desperately needed. One hypothesis that could—at least in part—explain the desolate response of PDAC to chemotherapy is the so-called cancer stem cell (CSC) concept, which attributes specific traits, such as chemoresistance, metastatic potential and a distinct metabolism to a small cellular subpopulation of the whole tumor. At the same time, however, some of these attributes could make CSCs more permissive for novel therapeutic strategies with compounds that are already in clinical use. Most recently, several publications have tried to enlighten the field with the idea of repurposing established drugs for antineoplastic use. As such, recycling drugs could present an intriguing and fast-track method with new therapeutic paradigms in anti-cancer and anti-CSC treatments. Here, we aim to summarize important aspects and novel findings of this emerging field.
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Giovannetti E, van der Borden CL, Frampton AE, Ali A, Firuzi O, Peters GJ. Never let it go: Stopping key mechanisms underlying metastasis to fight pancreatic cancer. Semin Cancer Biol 2017; 44:43-59. [PMID: 28438662 DOI: 10.1016/j.semcancer.2017.04.006] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/12/2017] [Accepted: 04/18/2017] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive neoplasm, predicted to become the second leading cause of cancer-related deaths before 2030. This dismal trend is mainly due to lack of effective treatments against its metastatic behavior. Therefore, a better understanding of the key mechanisms underlying metastasis should provide new opportunities for therapeutic purposes. Genomic analyses revealed that aberrations that fuel PDAC tumorigenesis and progression, such as SMAD4 loss, are also implicated in metastasis. Recently, microRNAs have been shown to play a regulatory role in the metastatic behavior of many tumors, including PDAC. In particular, miR-10 and miR-21 have appeared as master regulators of the metastatic program, while members of the miR-200 family are involved in the epithelial-to-mesenchymal switch, favoring cell migration and invasiveness. Several studies have also found a close relationship between cancer stem cells (CSCs) and biological features of metastasis, and the CSC markers ALDH1, ABCG2 and c-Met are expressed at high levels in metastatic PDAC cells. Emerging evidence reveals that exosomes are involved in the modulation of the tumor microenvironment and can initiate PDAC pre-metastatic niche formation in the liver and lungs. In this review, we provide an overview of the role of all these pivotal factors in the metastatic behavior of PDAC, and discuss their potential exploitation in the clinic to improve current therapeutics and identify new drug targets.
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Affiliation(s)
- E Giovannetti
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands; Cancer Pharmacology Lab, AIRC Start Up Unit, University of Pisa, Pisa, Italy
| | - C L van der Borden
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - A E Frampton
- HPB Surgical Unit, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, London, UK
| | - A Ali
- Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, KP, Pakistan; Institute of Cancer Sciences, University of Glasgow, UK
| | - O Firuzi
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - G J Peters
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
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Agliano A, Calvo A, Box C. The challenge of targeting cancer stem cells to halt metastasis. Semin Cancer Biol 2017; 44:25-42. [PMID: 28323021 DOI: 10.1016/j.semcancer.2017.03.003] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 03/10/2017] [Accepted: 03/13/2017] [Indexed: 12/21/2022]
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46
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Gao J, Long B, Wang Z. Role of Notch signaling pathway in pancreatic cancer. Am J Cancer Res 2017; 7:173-186. [PMID: 28337369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 10/12/2016] [Indexed: 09/28/2022] Open
Abstract
Pancreatic cancer (PC) is one of the highly aggressive malignancies in the United States. It has been shown that multiple signaling pathways are involved in the pathogenesis of PC, such as JNK, PI3K/AKT, Rho GTPase, Hedgehog (Hh) and Skp2. In recent years, accumulated evidence has demonstrated that Notch signaling pathway plays critical roles in the development and progression of PC. Therefore, in this review we discuss the recent literature regarding the function and regulation of Notch in the pathogenesis of PC. Moreover, we describe that Notch signaling pathway could be down-regulated by its inhibitors or natural compounds, which could be a novel approach for the treatment of PC patients.
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Affiliation(s)
- Jiankun Gao
- Sichuan College of Tranditional Chinese Medicine Mianyang, Sichuan, China
| | - Bo Long
- Department of Infectious Diseases, Mianyang 404 Hospital Mianyang, Sichuan, China
| | - Zhiwei Wang
- The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow UniversitySuzhou 215123, China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolMA 02215, USA
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Xiao W, Gao Z, Duan Y, Yuan W, Ke Y. Notch signaling plays a crucial role in cancer stem-like cells maintaining stemness and mediating chemotaxis in renal cell carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:41. [PMID: 28279221 PMCID: PMC5345133 DOI: 10.1186/s13046-017-0507-3] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 02/18/2017] [Indexed: 02/06/2023]
Abstract
Background Cancer stem cells (CSCs) are correlated with the initiation, chemoresistance and relapse of tumors. Notch pathway has been reported to function in CSCs maintenance, but whether it is involved in renal cell carcinoma (RCC) CSCs maintaining stemness remain unclear. This study aims to explore the effect of Notch pathway on stemness of CSCs in RCC and the underlying mechanisms. Methods The CD133+/CD24+ cells were isolated from RCC ACHN and Caki-1 cell line using Magnetic-activated cell sorting and identified by Flow cytometry analysis. RT-PCR and immunoblot analyses were used for determining the stemness maker expression. The effect of Notch pathway on function of CSCs was assessed by self-renewal ability, chemosensitivity, invasive and migratory ability tumorigenicity in vivo using soft agar colony formation assay, sphere-forming assay, MTT assay, Transwell assay. Results Here, we found that the sorted CD133+/CD24+cells possessed elevated stemness maker CTR2, BCL-2, MDR1, OCT-4, KLF4, compared with parental cells, as well as enhanced self-renewal ability, stronger resistance to cisplatin and sorafenib, increased invasion and migration, and higher tumorigenesis in vivo, suggesting the CD133+/CD24+ cells have the stem-like characteristics of CSCs and thus identified as RCC CSCs. Then the enhanced notch1, notch2, Jagged1, Jagged2, DLL1 and DLL4 expression were detected in RCC CSCs and blockage of Notch1 or notch2 using pharmacological inhibitor MRK-003 or its endogenous inhibitor Numb resulted in loss of its stemness features: self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis in vivo. Moreover, it is confirmed that overexpression of notch1 up-regulated CXCR4 inRCC CSCs and augmented SDF-1-induced chemotaxis in RCC CSCs in vitro, which could be rescued when treatment of CXCR4 inhibitor, suggesting that notch signaling promotes the chemotaxis of RCC CSCs by SDF-1/CXCR4 axis. Conclusions Our results provide a new mechanism of RCC CSCs maintaining stemness via notch pathway as well as a potential therapeutic target in human RCC.
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Affiliation(s)
- Wei Xiao
- Department of Urology, Hunan Provincial People's Hospital, JiefangWest Road 61, Changsha, Hunan, China.
| | - Zhiyong Gao
- Department of Urology, Hunan Provincial People's Hospital, JiefangWest Road 61, Changsha, Hunan, China
| | - Yixing Duan
- Department of Urology, Hunan Provincial People's Hospital, JiefangWest Road 61, Changsha, Hunan, China
| | - Wuxiong Yuan
- Department of Urology, Hunan Provincial People's Hospital, JiefangWest Road 61, Changsha, Hunan, China
| | - Yang Ke
- Department of Urology, Hunan Provincial People's Hospital, JiefangWest Road 61, Changsha, Hunan, China
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