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Kubatka P, Bojkova B, Nosalova N, Huniadi M, Samuel SM, Sreenesh B, Hrklova G, Kajo K, Hornak S, Cizkova D, Bubnov R, Smokovski I, Büsselberg D, Golubnitschaja O. Targeting the MAPK signaling pathway: implications and prospects of flavonoids in 3P medicine as modulators of cancer cell plasticity and therapeutic resistance in breast cancer patients. EPMA J 2025; 16:437-463. [PMID: 40438489 PMCID: PMC12106287 DOI: 10.1007/s13167-025-00407-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 03/24/2025] [Indexed: 04/21/2025]
Abstract
Cancer drug resistance poses a significant challenge in oncology, primarily driven by cancer cell plasticity, which promotes tumor initiation, progression, metastasis, and therapeutic evasion in many different cancers. Breast cancers (BCs) are a prominent example of that, with an estimated 2.3 million new cases and 670,000 BC-related deaths registered worldwide annually. Triple-negative BC is especially challenging for treatments demonstrating particularly aggressive disease course, an early manifestation of metastatic disease, frequent drug-resistant cancer types, and poor individual outcomes. Although chemosensitizing agents have been developed, their clinical utility in oncology remains unproven. The mitogen-activated protein kinase (MAPK) pathway is considered a critical regulator of intracellular and extracellular signaling highly relevant for both - genetic and epigenetic modifications. Dysregulation of the MAPK signaling pathways plays a significant role in conferring chemoresistance in BC. Contextually, targeting the MAPK pathway represents a promising strategy for overcoming drug resistance and enhancing the therapeutic efficacy of anticancer agents in BC treatment. On the other hand, flavonoids, a prominent class of phytochemicals, are key modulators of MAPK signaling. Flavonoids interact with the ERK, JNK, p38, and ERK5 pathways of the MAPK signaling cascade and present a promising avenue for developing novel anti-cancer therapies and re-sensitizing agents for the treatment of BC. Compounds such as quercetin, kaempferol, genistein, luteolin, myricetin, EGCG, baicalein, baicalin, nobiletin, morin, delphinidin, acacetin, isorhamnetin, apigenin, silymarin, among others, have been identified as specific modulators of MAPK signaling, exerting complex downstream effects in BC cells increasing therewith drug efficacy and suppressing tumor growth and aggressivity. These properties reflect mechanisms of great clinical relevance to overcome therapeutic resistance in overall BC management. This article highlights corresponding mechanisms and provides clinically relevant illustrations in the framework of 3P medicine for primary (protection of individuals at high risk against health-to-disease transition) and secondary care (protection against metastatic BC progression). 3PM novelty makes good use of patient phenotyping and stratification, predictive multi-level diagnostics, and application of Artificial Intelligence (AI) tools to the individualized interpretation of big data - all proposed for cost-effective treatments tailored to individualized patient profiles with clear benefits to patients and advanced BC management.
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Affiliation(s)
- Peter Kubatka
- Centre of Experimental and Clinical Regenerative Medicine, Small Animal Clinic, University of Veterinary Medicine and Pharmacy, 041 81 Kosice, Slovakia
- Department of Biology and Ecology, Pedagogical Faculty, Catholic University in Ružomberok, 034 01 Ružomberok, Slovakia
| | - Bianka Bojkova
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Košice, 040 01 Slovakia
| | - Natalia Nosalova
- Centre of Experimental and Clinical Regenerative Medicine, Small Animal Clinic, University of Veterinary Medicine and Pharmacy, 041 81 Kosice, Slovakia
| | - Mykhailo Huniadi
- Centre of Experimental and Clinical Regenerative Medicine, Small Animal Clinic, University of Veterinary Medicine and Pharmacy, 041 81 Kosice, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, 24144 Doha, Qatar
| | - Bini Sreenesh
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, 24144 Doha, Qatar
| | - Gabriela Hrklova
- Department of Biology and Ecology, Pedagogical Faculty, Catholic University in Ružomberok, 034 01 Ružomberok, Slovakia
| | - Karol Kajo
- Department of Pathology, St. Elisabeth Oncology Institute, 812 50 Bratislava, Slovakia
| | - Slavomir Hornak
- Small Animal Clinic, University of Veterinary Medicine and Pharmacy, 041 81 Kosice, Slovakia
| | - Dasa Cizkova
- Centre of Experimental and Clinical Regenerative Medicine, Small Animal Clinic, University of Veterinary Medicine and Pharmacy, 041 81 Kosice, Slovakia
- Institute of Neuroimmunology, Slovak Academy of Sciences, 845 10 Bratislava, Slovakia
| | - Rostyslav Bubnov
- Clinical Hospital “Pheophania”, Kyiv, Ukraine
- Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - Ivica Smokovski
- University Clinic of Endocrinology, Diabetes and Metabolic Disorders, Skopje, North Macedonia
- Faculty of Medical Sciences, University Goce Delcev, Stip, North Macedonia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, 24144 Doha, Qatar
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
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Zou Y, Shi H, Lin H, Wang X, Wang G, Gao Y, Yi F, Yin Y, Li D, Li M. The abrogation of GRP78 sensitizes liver cancer cells to lysionotin by enhancing ER stress-mediated pro-apoptotic pathway. Cell Stress Chaperones 2023; 28:409-422. [PMID: 37326827 PMCID: PMC10352479 DOI: 10.1007/s12192-023-01358-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/14/2023] [Accepted: 06/02/2023] [Indexed: 06/17/2023] Open
Abstract
Glucose-regulated protein 78 (GRP78) is frequently and highly expressed in various human malignancies and protects cancer cells against apoptosis induced by multifarious stresses, particularly endoplasmic reticulum stress (ER stress). The inhibition of GRP78 expression or activity could enhance apoptosis induced by anti-tumor drugs or compounds. Herein, we will evaluate the efficacy of lysionotin in the treatment of human liver cancer as well as the molecular mechanism. Moreover, we will examine whether inhibition of GRP78 enhanced the sensitivity of hepatocellular carcinoma cells to lysionotin. We found that lysionotin significantly suppressed proliferation and induced apoptosis of liver cancer cells. TEM showed that lysionotin-treated liver cancer cells showed an extensively distended and dilated endoplasmic reticulum lumen. Meanwhile, the levels of the ER stress hallmark GRP78 and UPR hallmarks (e.g., IRE1α and CHOP) were significantly increased in response to lysionotin treatment in liver cancer cells. Moreover, the reactive oxygen species (ROS) scavenger NAC and caspase-3 inhibitor Ac-DEVD-CHO visibly attenuated the induction of GRP78 and attenuated the decrease in cell viability induced by lysionotin. More importantly, the knockdown of GRP78 expression by siRNAs or treatment with EGCG, both induced remarkable increase in lysionotin-induced PARP and pro-caspase-3 cleavage and JNK phosphorylation. In addition, knockdown of GRP78 expression by siRNA or suppression GRP78 activity by EGCG both significantly improved the effectiveness of lysionotin. These data indicated that pro-survival GRP78 induction may contribute to lysionotin resistance. The combination of EGCG and lysionotin is suggested to represent a novel approach in cancer chemo-prevention and therapeutics.
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Affiliation(s)
- Ying Zou
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Hewen Shi
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Haiyan Lin
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Xiaoxue Wang
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Guoli Wang
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China
| | - Yijia Gao
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Fan Yi
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Yancun Yin
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China.
| | - Defang Li
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China.
- Collaborative innovation platform for modernization and industrialization of regional characteristic traditional Chinese medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China.
| | - Minjing Li
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China.
- Collaborative innovation platform for modernization and industrialization of regional characteristic traditional Chinese medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, 264003, Shandong, People's Republic of China.
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Du S, Liu Y, Yuan Y, Wang Y, Chen Y, Wang S, Chi Y. Advances in the study of HSP70 inhibitors to enhance the sensitivity of tumor cells to radiotherapy. Front Cell Dev Biol 2022; 10:942828. [PMID: 36036010 PMCID: PMC9399644 DOI: 10.3389/fcell.2022.942828] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
The 70 kDa heat shock protein (HSP70) is one of the most conserved proteins and a ubiquitous molecular chaperone that plays a role in the folding, remodeling, and degradation of various proteins to maintain proteostasis. It has been shown that HSP70 is abundantly expressed in cancer and enhances tumor resistance to radiotherapy by inhibiting multiple apoptotic pathways, such as interfering with the cellular senescence program, promoting angiogenesis, and supporting metastasis. Thus, HSP70 provides an effective target for enhancing the effects of radiation therapy in the clinical management of cancer patients. Inhibition of HSP70 enhances the radiation-induced tumor-killing effect and thus improves the efficacy of radiotherapy. This article reviews the sensitivity of Hsp70 and its related inhibitors to radiotherapy of tumor cells.
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Affiliation(s)
- Sihan Du
- School of Medical Imaging, Weifang Medical University, Weifang, Shandong, China
| | - Ying Liu
- School of Medical Imaging, Weifang Medical University, Weifang, Shandong, China
| | - Yuan Yuan
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Yuran Wang
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Yanfang Chen
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Shuai Wang
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
- *Correspondence: Shuai Wang, ; Yuhua Chi,
| | - Yuhua Chi
- Department of General Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
- *Correspondence: Shuai Wang, ; Yuhua Chi,
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Hung SW, Li Y, Chen X, Chu KO, Zhao Y, Liu Y, Guo X, Man GCW, Wang CC. Green Tea Epigallocatechin-3-Gallate Regulates Autophagy in Male and Female Reproductive Cancer. Front Pharmacol 2022; 13:906746. [PMID: 35860020 PMCID: PMC9289441 DOI: 10.3389/fphar.2022.906746] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/17/2022] [Indexed: 11/29/2022] Open
Abstract
With a rich abundance of natural polyphenols, green tea has become one of the most popular and healthiest nonalcoholic beverages being consumed worldwide. Epigallocatechin-3-gallate (EGCG) is the predominant catechin found in green tea, which has been shown to promote numerous health benefits, including metabolic regulation, antioxidant, anti-inflammatory, and anticancer. Clinical studies have also shown the inhibitory effects of EGCG on cancers of the male and female reproductive system, including ovarian, cervical, endometrial, breast, testicular, and prostate cancers. Autophagy is a natural, self-degradation process that serves important functions in both tumor suppression and tumor cell survival. Naturally derived products have the potential to be an effective and safe alternative in balancing autophagy and maintaining homeostasis during tumor development. Although EGCG has been shown to play a critical role in the suppression of multiple cancers, its role as autophagy modulator in cancers of the male and female reproductive system remains to be fully discussed. Herein, we aim to provide an overview of the current knowledge of EGCG in targeting autophagy and its related signaling mechanism in reproductive cancers. Effects of EGCG on regulating autophagy toward reproductive cancers as a single therapy or cotreatment with other chemotherapies will be reviewed and compared. Additionally, the underlying mechanisms and crosstalk of EGCG between autophagy and other cellular processes, such as reactive oxidative stress, ER stress, angiogenesis, and apoptosis, will be summarized. The present review will help to shed light on the significance of green tea as a potential therapeutic treatment for reproductive cancers through regulating autophagy.
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Affiliation(s)
- Sze Wan Hung
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Yiran Li
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiaoyan Chen
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Department of Obstetrics and Gynaecology, Shenzhen Baoan Women’s and Children’s Hospital, Shenzhen University, Shenzhen, China
| | - Kai On Chu
- Department of Ophthalmology and Visual Sciences, Hong Kong Eye Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Yiwei Zhao
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Department of Obstetrics and Gynecology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yingyu Liu
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Department of Obstetrics and Gynaecology, Shenzhen Baoan Women’s and Children’s Hospital, Shenzhen University, Shenzhen, China
| | - Xi Guo
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Gene Chi-Wai Man
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Department of Orthopaedics and Traumatology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- *Correspondence: Gene Chi-Wai Man, ; Chi Chiu Wang,
| | - Chi Chiu Wang
- Department of Obstetrics and Gynaecology, The Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences; School of Biomedical Sciences; and Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- *Correspondence: Gene Chi-Wai Man, ; Chi Chiu Wang,
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Persico M, Abbruzzese C, Matteoni S, Matarrese P, Campana AM, Villani V, Pace A, Paggi MG. Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma. Cells 2022; 11:263. [PMID: 35053377 PMCID: PMC8773942 DOI: 10.3390/cells11020263] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 02/01/2023] Open
Abstract
Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease.
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Affiliation(s)
- Michele Persico
- Cellular Networks and Molecular Therapeutic Targets, Proteomics Unit, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy; (M.P.); (C.A.); (S.M.)
| | - Claudia Abbruzzese
- Cellular Networks and Molecular Therapeutic Targets, Proteomics Unit, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy; (M.P.); (C.A.); (S.M.)
| | - Silvia Matteoni
- Cellular Networks and Molecular Therapeutic Targets, Proteomics Unit, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy; (M.P.); (C.A.); (S.M.)
| | - Paola Matarrese
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, 00162 Rome, Italy;
| | - Anna Maria Campana
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA;
| | - Veronica Villani
- Neuro-Oncology, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy; (V.V.); (A.P.)
| | - Andrea Pace
- Neuro-Oncology, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy; (V.V.); (A.P.)
| | - Marco G. Paggi
- Cellular Networks and Molecular Therapeutic Targets, Proteomics Unit, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy; (M.P.); (C.A.); (S.M.)
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Kabakov AE, Gabai VL. HSP70s in Breast Cancer: Promoters of Tumorigenesis and Potential Targets/Tools for Therapy. Cells 2021; 10:cells10123446. [PMID: 34943954 PMCID: PMC8700403 DOI: 10.3390/cells10123446] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/25/2021] [Accepted: 12/03/2021] [Indexed: 12/20/2022] Open
Abstract
The high frequency of breast cancer worldwide and the high mortality among women with this malignancy are a serious challenge for modern medicine. A deeper understanding of the mechanisms of carcinogenesis and emergence of metastatic, therapy-resistant breast cancers would help development of novel approaches to better treatment of this disease. The review is dedicated to the role of members of the heat shock protein 70 subfamily (HSP70s or HSPA), mainly inducible HSP70, glucose-regulated protein 78 (GRP78 or HSPA5) and GRP75 (HSPA9 or mortalin), in the development and pathogenesis of breast cancer. Various HSP70-mediated cellular mechanisms and pathways which contribute to the oncogenic transformation of mammary gland epithelium are reviewed, as well as their role in the development of human breast carcinomas with invasive, metastatic traits along with the resistance to host immunity and conventional therapeutics. Additionally, intracellular and cell surface HSP70s are considered as potential targets for therapy or sensitization of breast cancer. We also discuss a clinical implication of Hsp70s and approaches to targeting breast cancer with gene vectors or nanoparticles downregulating HSP70s, natural or synthetic (small molecule) inhibitors of HSP70s, HSP70-binding antibodies, HSP70-derived peptides, and HSP70-based vaccines.
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Affiliation(s)
- Alexander E. Kabakov
- Department of Radiation Biochemistry, A. Tsyb Medical Radiological Research Center—Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Koroleva 4, 249036 Obninsk, Russia;
| | - Vladimir L. Gabai
- CureLab Oncology Inc., Dedham, MA 02026, USA
- Correspondence: ; Tel.: +1-617-319-7314
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Zhang W, Zhang W, Sun L, Xiang L, Lai X, Li Q, Sun S. The effects and mechanisms of epigallocatechin-3-gallate on reversing multidrug resistance in cancer. Trends Food Sci Technol 2019. [DOI: 10.1016/j.tifs.2019.09.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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de Oliveira MB, Sanson LF, Eugenio AI, Barbosa-Dantas RS, Colleoni GW. Stew in its Own Juice: Protein Homeostasis Machinery Inhibition Reduces Cell Viability in Multiple Myeloma Cell Lines. Curr Mol Med 2019; 19:112-119. [DOI: 10.2174/1566524019666190305134441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 02/19/2019] [Accepted: 02/26/2019] [Indexed: 02/05/2023]
Abstract
Introduction:Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).Methods:We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.Results:For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.Conclusion:Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.
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Affiliation(s)
- Mariana B. de Oliveira
- Clinical and Experimental Oncology Department, Universidade Federal de Sao Paulo, Sao Paulo, UNIFESP, Brazil
| | - Luiz F.G. Sanson
- Clinical and Experimental Oncology Department, Universidade Federal de Sao Paulo, Sao Paulo, UNIFESP, Brazil
| | - Angela I.P. Eugenio
- Clinical and Experimental Oncology Department, Universidade Federal de Sao Paulo, Sao Paulo, UNIFESP, Brazil
| | - Rebecca S.S. Barbosa-Dantas
- Clinical and Experimental Oncology Department, Universidade Federal de Sao Paulo, Sao Paulo, UNIFESP, Brazil
| | - Gisele W.B. Colleoni
- Clinical and Experimental Oncology Department, Universidade Federal de Sao Paulo, Sao Paulo, UNIFESP, Brazil
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Twayana KS, Ravanan P. Eukaryotic cell survival mechanisms: Disease relevance and therapeutic intervention. Life Sci 2018; 205:73-90. [PMID: 29730169 DOI: 10.1016/j.lfs.2018.05.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/17/2018] [Accepted: 05/01/2018] [Indexed: 01/10/2023]
Abstract
Cell responds to stress by activating various modes of stress responses which aim for minimal damage to cells and speedy recovery from the insults. However, unresolved stresses exceeding the tolerance limit lead to cell death (apoptosis, autophagy etc.) that helps to get rid of damaged cells and protect cell integrity. Furthermore, aberrant stress responses are the hallmarks of several pathophysiologies (neurodegeneration, metabolic diseases, cancer etc.). The catastrophic remodulation of stress responses is observed in cancer cells in favor of their uncontrolled growth. Whereas pro-survival stress responses redirected to death signaling provokes excessive cell death in neurodegeneration. Clear understanding of such mechanistic link to disease progression is required in order to modulate these processes for new therapeutic targets. The current review explains this with respect to novel drug discoveries and other breakthroughs in therapeutics.
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Affiliation(s)
- Krishna Sundar Twayana
- Apoptosis and Cell Survival Research Laboratory, Department of Biosciences, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu-632014, India
| | - Palaniyandi Ravanan
- Apoptosis and Cell Survival Research Laboratory, Department of Biosciences, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu-632014, India.
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Abstract
Heat shock protein 70 (Hsp70) is the most ubiquitous stress-inducible chaperone. It accumulates in the cells in response to a wide variety of physiological and environmental insults including anticancer chemotherapy, thus allowing the cell to survive to lethal conditions. Intracellular Hsp70 is viewed as a cytoprotective protein. Indeed, this protein can inhibit key effectors of the apoptotic and autophagy machineries. In cancer cells, the expression of Hsp70 is abnormally high, and Hsp70 may participate in oncogenesis and in resistance to chemotherapy. In rodent models, Hsp70 overexpression increases tumor growth and metastatic potential. Depletion or inhibition of Hsp70 frequently reduces the size of the tumors and can even cause their complete involution. However, HSP70 is also found in the extra-cellular space where it may signal via membrane receptors or endosomes to alter gene transcription and cellular function. Overall, Hsp70 extracellular function is believed to be immnunogenic and the term chaperokine to define the extracellular chaperones such as Hsp70 has been advanced. In this chapter the knowledge to date, as well as some emerging paradigms about the intra- and extra-cellular functions of Hsp70, are presented. The strategies targeting Hsp70 that are being developed in cancer therapy will also be discussed.
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Affiliation(s)
- Christophe Boudesco
- Univ. Bourgogne Franche-Comté, LNC UMR1231, Dijon, France
- INSERM, LNC UMR1231, Dijon, France
- Equipe Labellisée par la Ligue Nationale Contre le Cancer, INSERM, LNC UMR1231, Dijon, France
- LipSTIC LabEx, Fondation de Coopération Scientifique Bourgogne Franche-Comté, Dijon, France
| | - Sebastien Cause
- Univ. Bourgogne Franche-Comté, LNC UMR1231, Dijon, France
- INSERM, LNC UMR1231, Dijon, France
- Equipe Labellisée par la Ligue Nationale Contre le Cancer, INSERM, LNC UMR1231, Dijon, France
- LipSTIC LabEx, Fondation de Coopération Scientifique Bourgogne Franche-Comté, Dijon, France
| | - Gaëtan Jego
- Univ. Bourgogne Franche-Comté, LNC UMR1231, Dijon, France.
- INSERM, LNC UMR1231, Dijon, France.
- Equipe Labellisée par la Ligue Nationale Contre le Cancer, INSERM, LNC UMR1231, Dijon, France.
- LipSTIC LabEx, Fondation de Coopération Scientifique Bourgogne Franche-Comté, Dijon, France.
| | - Carmen Garrido
- Univ. Bourgogne Franche-Comté, LNC UMR1231, Dijon, France.
- INSERM, LNC UMR1231, Dijon, France.
- Equipe Labellisée par la Ligue Nationale Contre le Cancer, INSERM, LNC UMR1231, Dijon, France.
- LipSTIC LabEx, Fondation de Coopération Scientifique Bourgogne Franche-Comté, Dijon, France.
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Avril T, Vauléon E, Chevet E. Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers. Oncogenesis 2017; 6:e373. [PMID: 28846078 PMCID: PMC5608920 DOI: 10.1038/oncsis.2017.72] [Citation(s) in RCA: 202] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 06/01/2017] [Accepted: 07/07/2017] [Indexed: 02/07/2023] Open
Abstract
The unfolded protein response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress. During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply) challenges, with which they must cope to survive. Moreover, chemotherapy represents an additional extrinsic challenge that cancer cells are facing and to which they adapt in the case of resistance. As of today, resistance to chemotherapy and targeted therapies is one of the important issues that oncologists have to deal with for treating cancer patients. In this review, we first describe the key molecular mechanisms controlling the UPR and their implication in solid cancers. Then, we review the literature that connects cancer chemotherapy resistance mechanisms and activation of the UPR. Finally, we discuss the possible applications of targeting the UPR to bypass drug resistance.
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Affiliation(s)
- T Avril
- INSERM U1242, 'Chemistry, Oncogenesis, Stress, Signaling', Université de Rennes 1, Rennes, France.,Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - E Vauléon
- INSERM U1242, 'Chemistry, Oncogenesis, Stress, Signaling', Université de Rennes 1, Rennes, France.,Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - E Chevet
- INSERM U1242, 'Chemistry, Oncogenesis, Stress, Signaling', Université de Rennes 1, Rennes, France.,Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
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12
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Ho CT, Shang HS, Chang JB, Liu JJ, Liu TZ. Folate deficiency-triggered redox pathways confer drug resistance in hepatocellular carcinoma. Oncotarget 2016; 6:26104-18. [PMID: 26327128 PMCID: PMC4694889 DOI: 10.18632/oncotarget.4422] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 06/17/2015] [Indexed: 02/07/2023] Open
Abstract
Patients with hepatocellular carcinoma (HCC) are prone to folate deficiency (FD). Here we showed that, in cell line-specific manner, FD caused resistance to FD-induced oxidative stress and multi-drug resistance (MDR). This resistance was due to upregulation of glucose-regulated protein 78 (GRP78) and Survivin. Using siRNA and Epigallocatechin gallate (EGCG), we found that GRP78 and Survivin cooperatively conferred MDR by decreasing FD-induced ROS generation. Our data showed that FD increases GRP78 and Survivin, which serve as ROS inhibitors, causing MDR in HCC. We suggest that folate supplementation may enhance the efficacy of chemotherapy.
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Affiliation(s)
- Chun-Te Ho
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hung-Sheng Shang
- Department of Pathology, National Defense Medical Center, Division of Clinical Pathology, Tri-Service General Hospital, Taipei, Taiwan
| | - Jin-Biou Chang
- Department of Pathology, National Defense Medical Center, Division of Clinical Pathology, Tri-Service General Hospital, Taipei, Taiwan
| | - Jun-Jen Liu
- School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan
| | - Tsan-Zon Liu
- Translational Research Laboratory, Cancer Center, Taipei Medical University and Hospital, Taipei, Taiwan
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13
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Kumar S, Stokes J, Singh UP, Scissum Gunn K, Acharya A, Manne U, Mishra M. Targeting Hsp70: A possible therapy for cancer. Cancer Lett 2016; 374:156-166. [PMID: 26898980 PMCID: PMC5553548 DOI: 10.1016/j.canlet.2016.01.056] [Citation(s) in RCA: 167] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 01/28/2016] [Accepted: 01/31/2016] [Indexed: 01/13/2023]
Abstract
In all organisms, heat-shock proteins (HSPs) provide an ancient defense system. These proteins act as molecular chaperones by assisting proper folding and refolding of misfolded proteins and aid in the elimination of old and damaged cells. HSPs include Hsp100, Hsp90, Hsp70, Hsp40, and small HSPs. Through its substrate-binding domains, Hsp70 interacts with wide spectrum of molecules, ranging from unfolded to natively folded and aggregated proteins, and provides cytoprotective role against various cellular stresses. Under pathophysiological conditions, the high expression of Hsp70 allows cells to survive with lethal injuries. Increased Hsp70, by interacting at several points on apoptotic signaling pathways, leads to inhibition of apoptosis. Elevated expression of Hsp70 in cancer cells may be responsible for tumorigenesis and for tumor progression by providing resistance to chemotherapy. In contrast, inhibition or knockdown of Hsp70 reduces the size of tumors and can cause their complete regression. Moreover, extracellular Hsp70 acts as an immunogen that participates in cross presentation of MHC-I molecules. The goals of this review are to examine the roles of Hsp70 in cancer and to present strategies targeting Hsp70 in the development of cancer therapeutics.
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Affiliation(s)
- Sanjay Kumar
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36101, USA
| | - James Stokes
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36101, USA
| | - Udai P Singh
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
| | - Karyn Scissum Gunn
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36101, USA
| | - Arbind Acharya
- Centre of Advance Study in Zoology, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Manoj Mishra
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36101, USA.
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14
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The PERKs of damage-associated molecular patterns mediating cancer immunogenicity: From sensor to the plasma membrane and beyond. Semin Cancer Biol 2015; 33:74-85. [PMID: 25882379 DOI: 10.1016/j.semcancer.2015.03.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 03/17/2015] [Accepted: 03/19/2015] [Indexed: 12/20/2022]
Abstract
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are emerging as key adaptation mechanisms in response to loss of proteostasis, with major cell autonomous and non-autonomous functions impacting cancer progression and therapeutic responses. In recent years, vital physiological roles of the ER in maintenance of proteostasis, Ca(2+) signaling and trafficking through the secretory pathway have emerged. Some of these functions have been shown to be decisive for mobilizing certain signals from injured/dying cancer cells in response to certain anticancer treatments, toward the plasma membrane and ultimately emit them into the extracellular environment, where they may act as danger signals. The spatiotemporally defined emission of these signals, better known as damage-associated molecular patterns (DAMPs), distinguishes this type of cancer cell death from physiological apoptosis, which is tolerogenic in nature, thereby enabling these dying cancer cells to alert the immune system and "re-activate" antitumor immunity. The emission of DAMPs, decisive for immunogenic cell death (ICD) and which include the ER chaperone calreticulin and ATP, is reliant on a danger signaling module induced by certain assorted anticancer treatments through oxidative-ER stress. The main focus of this review is to discuss the emerging role of ER-stress regulated pathways and processes in danger signaling thereby regulating the cancer cell-immune cell interface by the extracellular emission of DAMPs. In particular, we discuss signaling contexts existing upstream and around PERK, a major ER-stress sensor in ICD context, which have not been emphatically discussed in the context of antitumor immunity and ICD up until now. Finally, we briefly discuss the pros and cons of targeting PERK in the context of ICD.
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15
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Li MJ, Yin YC, Wang J, Jiang YF. Green tea compounds in breast cancer prevention and treatment. World J Clin Oncol 2014; 5:520-528. [PMID: 25114865 PMCID: PMC4127621 DOI: 10.5306/wjco.v5.i3.520] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Revised: 02/12/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the most common cancer among women. In recent years, many in vitro and in vivo studies indicate that green tea possesses anti-cancer effects. The epidemiological studies, however, have produced inconclusive results in humans. Likewise, results from animal models about the preventive or therapeutic effects of green tea components are inconclusive. The mechanisms by which green tea intake may influence the risk of breast cancer in humans remain elusive mechanisms by which green tea intake may influence. Here, we review recent studies of green tea polyphenols and their applications in the prevention and treatment of breast cancer. Furthermore, we discuss the effect of green tea components on breast cancer by reviewing epidemiological studies, animal model studies and clinical trials. At last, we discuss the mechanisms by which green tea components suppress the development and recurrence of breast cancer. A better understanding of the mechanisms will improve the utilization of green tea in breast cancer prevention and therapy and pave the way to novel prevention and treatment strategies for breast cancer.
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16
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Feng C, He K, Zhang C, Su S, Li B, Li Y, Duan CY, Chen S, Chen R, Liu Y, Li H, Wei M, Xia X, Dai R. JNK contributes to the tumorigenic potential of human cholangiocarcinoma cells through the mTOR pathway regulated GRP78 induction. PLoS One 2014; 9:e90388. [PMID: 24587347 PMCID: PMC3938720 DOI: 10.1371/journal.pone.0090388] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 01/28/2014] [Indexed: 12/14/2022] Open
Abstract
Less is known about the roles of c-Jun N-terminal kinase (JNK) in cholangiocarcinoma (CCA). Here, we report that JNK exerts its oncogenic action in human CCA cells, partially due to the mammalian target of rapamycin (mTOR) pathway regulated glucose-regulated protein 78 (GRP78) induction. In human CCA cells, the phosphorylation of eukaryotic initiation factor alpha (eIF2α) results in the accumulation of activating transcription factor 4 (ATF4) and GRP78 independent of unfolded protein response (UPR). Suppression of GRP78 expression decreases the proliferation and invasion of human CCA cells. It's notable that mTOR is required for eIF2α phosphorylation-induced ATF4 and GRP78 expression. Importantly, JNK promotes eIF2α/ATF4-mediated GRP78 induction through regulating the activity of mTOR. Thus, our study implicates JNK/mTOR signaling plays an important role in cholangiocarcinogenesis, partially through promoting the eIF2α/ATF4/GRP78 pathway.
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Affiliation(s)
- Chunhong Feng
- Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China
| | - Kai He
- Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China
| | - Chunyan Zhang
- Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China
| | - Song Su
- Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China
| | - Bo Li
- Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China
| | - Yuxiao Li
- Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China
| | - Chun-Yan Duan
- Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China
| | - Shaokun Chen
- Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China
| | - Run Chen
- Department of Public Health, Luzhou Medical College, Luzhou, Sichuan, China
| | - Youping Liu
- Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China
| | - Hong Li
- Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China
| | - Mei Wei
- Affiliated Hospital of Chinese Traditional Medicine, Luzhou Medical College, Luzhou, Sichuan, China
| | - Xianming Xia
- Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China
| | - Rongyang Dai
- Department of Hepatobiliary Surgery of the Affiliated Hospital, Luzhou Medical College, Luzhou, Sichuan, China
- Department of Biochemistry and Molecular Biology, Luzhou Medical College, Luzhou, Sichuan, China
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17
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Miao YR, Eckhardt BL, Cao Y, Pasqualini R, Argani P, Arap W, Ramsay RG, Anderson RL. Inhibition of established micrometastases by targeted drug delivery via cell surface-associated GRP78. Clin Cancer Res 2013; 19:2107-16. [PMID: 23470966 DOI: 10.1158/1078-0432.ccr-12-2991] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE The major cause of morbidity in breast cancer is development of metastatic disease, for which few effective therapies exist. Because tumor cell dissemination is often an early event in breast cancer progression and can occur before diagnosis, new therapies need to focus on targeting established metastatic disease in secondary organs. We report an effective therapy based on targeting cell surface-localized glucose-regulated protein 78 (GRP78). GRP78 is expressed normally in the endoplasmic reticulum, but many tumors and disseminated tumor cells are subjected to environmental stresses and exhibit elevated levels of GRP78, some of which are localized at the plasma membrane. EXPERIMENTAL DESIGN AND RESULTS Here, we show that matched primary tumors and metastases from patients who died from advanced breast cancer also express high levels of GRP78. We used a peptidomimetic targeting strategy that uses a known GRP78-binding peptide fused to a proapoptotic moiety [designated bone metastasis targeting peptide 78 (BMTP78)] and show that it can selectively kill breast cancer cells that express surface-localized GRP78. Furthermore, in preclinical metastasis models, we show that administration of BMTP78 can inhibit primary tumor growth as well as prolong overall survival by reducing the extent of outgrowth of established lung and bone micrometastases. CONCLUSIONS The data presented here provide strong evidence that it is possible to induce cell death in established micrometastases by peptide-mediated targeting of cell surface-localized GRP in advanced breast cancers. The significance to patients with advanced breast cancer of a therapy that can reduce established metastatic disease should not be underestimated.
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Affiliation(s)
- Yu Rebecca Miao
- Metastasis Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
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18
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Inoue H, Maeda-Yamamoto M, Nesumi A, Murakami A. Delphinidin-3-O-galactoside protects mouse hepatocytes from (−)-epigallocatechin-3-gallate–induced cytotoxicity via up-regulation of heme oxygenase-1 and heat shock protein 70. Nutr Res 2012; 32:357-64. [DOI: 10.1016/j.nutres.2012.04.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 03/15/2012] [Accepted: 04/03/2012] [Indexed: 12/23/2022]
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19
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The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene 2012; 32:805-18. [PMID: 22508478 DOI: 10.1038/onc.2012.130] [Citation(s) in RCA: 454] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer progression is characterized by rapidly proliferating cancer cells that are in need of increased protein synthesis. Therefore, enhanced endoplasmic reticulum (ER) activity is required to facilitate the folding, assembly and transportation of membrane and secretory proteins. These functions are carried out by ER chaperones. It is now becoming clear that the ER chaperones have critical functions outside of simply facilitating protein folding. For example, cancer progression requires glucose regulated protein (GRP) 78 for cancer cell survival and proliferation, as well as angiogenesis in the microenvironment. GRP78 can translocate to the cell surface acting as a receptor regulating oncogenic signaling and cell viability. Calreticulin, another ER chaperone, can translocate to the cell surface of apoptotic cancer cells and induce immunogenic cancer cell death and antitumor responses in vivo. Tumor-secreted GRP94 has been shown to elicit antitumor immune responses when used as antitumor vaccines. Protein disulfide isomerase is another ER chaperone that demonstrates pro-oncogenic and pro-survival functions. Because of intrinsic alterations of cellular metabolism and extrinsic factors in the tumor microenvironment, cancer cells are under ER stress, and they respond to this stress by activating the unfolded protein response (UPR). Depending on the severity and duration of ER stress, the signaling branches of the UPR can activate adaptive and pro-survival signals, or induce apoptotic cell death. The protein kinase RNA-like ER kinase signaling branch of the UPR has a dual role in cancer proliferation and survival, and is also required for ER stress-induced autophagy. The activation of the inositol-requiring kinase 1α branch promotes tumorigenesis, cancer cell survival and regulates tumor invasion. In summary, perturbance of ER homeostasis has critical roles in tumorigenesis, and therapeutic modulation of ER chaperones and/or UPR components presents potential antitumor treatments.
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20
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Sun X, Huo X, Luo T, Li M, Yin Y, Jiang Y. The anticancer flavonoid chrysin induces the unfolded protein response in hepatoma cells. J Cell Mol Med 2012; 15:2389-98. [PMID: 21199322 PMCID: PMC3822950 DOI: 10.1111/j.1582-4934.2010.01244.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Chrysin is a natural and biologically active flavonoid with anticancer effects. However, little is known about the adaptive response of cancer cells to chrysin. Chrysin reportedly has proteasome inhibitor activity. Previous studies demonstrated that proteasome inhibitors might induce endoplasmic reticulum (ER) stress response. In this study, we aimed to determine the effects of chrysin on hepatoma cells and roles of the ER-resident protein GRP78 (glucose-regulated protein 78) in its action. Also, we investigated the effects of green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), a natural GRP78 inhibitor, on the sensitivity of hepatoma cells to chrysin. Here, we report that chrysin inhibits hepatoma cells growth and induces apoptosis in a dose-dependent manner. Chrysin induces GRP78 overexpression, X-box binding protein-1 splicing and eukaryotic initiation factor 2α phosphorylation, hallmarks of the unfolded protein response. GRP78 knockdown potentiates chrysin-induced caspase-7 cleavage in hepatoma cells and enhances chrysin-induced apoptosis. EGCG overcomes chrysin-induced GRP78 expression. Combination of EGCG potentiates chrysin-induced caspase-7 and poly (ADP-ribose) polymerase (PARP) cleavage. Finally, EGCG sensitizes hepatoma cells to chrysin through caspase-mediated apoptosis. These data suggest that chrysin triggers the unfolded protein response. Abrogation of GRP78 induction may improve the anticancer effects of chrysin. Combination of EGCG and chrysin represents a new regimen for cancer chemoprevention and therapeutics.
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Affiliation(s)
- Xiangming Sun
- State Key Laboratory of Biotherapy, Section of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, China
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21
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Li Z, Li Z. Glucose regulated protein 78: a critical link between tumor microenvironment and cancer hallmarks. Biochim Biophys Acta Rev Cancer 2012; 1826:13-22. [PMID: 22426159 DOI: 10.1016/j.bbcan.2012.02.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Revised: 02/26/2012] [Accepted: 02/27/2012] [Indexed: 12/27/2022]
Abstract
Glucose regulated protein 78 (GRP78) has long been recognized as a molecular chaperone in the endoplasmic reticulum (ER) and can be induced by the ER stress response. Besides its location in the ER, GRP78 has been found to be present in cell plasma membrane, cytoplasm, mitochondria, nucleus as well as cellular secretions. GRP78 is implicated in tumor cell proliferation, apoptosis resistance, immune escape, metastasis and angiogenesis, and its elevated expression usually correlates with a variety of tumor microenvironmental stresses, including hypoxia, glucose deprivation, lactic acidosis and inflammatory response. GRP78 protein acts as a centrally located sensor of stress, which feels and adapts to the alteration in the tumor microenvironment. This article reviews the potential contributions of GRP78 to the acquisition of cancer hallmarks based on intervening in stress responses caused by tumor niche alterations. The paper also introduces several potential GRP78 relevant targeted therapies.
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Affiliation(s)
- Zongwei Li
- Institute of Biotechnology, The Key Laboratory of Clinical Biology and Molecular Engineering of Education Ministry, Shanxi University, 030006 Taiyuan, PR China
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22
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Siebke C, James TC, Cummins R, O’Grady T, Kay E, Bond U. Phage display biopanning identifies the translation initiation and elongation factors (IF1α-3 and eIF-3) as components of Hsp70-peptide complexes in breast tumour cells. Cell Stress Chaperones 2012; 17:145-56. [PMID: 22002548 PMCID: PMC3273561 DOI: 10.1007/s12192-011-0295-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Revised: 09/16/2011] [Accepted: 09/20/2011] [Indexed: 10/16/2022] Open
Abstract
The heat shock protein, HSP70, is over-expressed in many tumours and acts at the crossroads of key intracellular processes in its role as a molecular chaperone. HSP70 associates with a vast array of peptides, some of which are antigenic and can mount adaptive immune responses against the tumour from which they are derived. The pool of peptides associated with HSP70 represents a unique barcode of protein metabolism in tumour cells. With a view to identifying unique protein targets that may be developed as tumour biomarkers, we used purified HSP70 and its associated peptide pool (HSP70-peptide complexes, HSP70-PCs) from different human breast tumour cell lines as targets for phage display biopanning. Our results show that HSP70-PCs from each cell line interact with unique sets of peptides within the phage display library. One of the peptides, termed IST, enriched in the biopanning process, was used in a 'pull-down' assay to identify the original protein from which the HSP70-associated peptides may have been derived. The eukaryotic translation initiation factor 3 (eIF-3), a member of the elongation factor EF1α family, and the HSP GRP78, were pulled down by the IST peptide. All of these proteins are known to be up-regulated in cancer cells. Immunohistochemical staining of tumour tissue microarrays showed that the peptide co-localised with HSP70 in breast tumour tissue. The data indicate that the reservoir of peptides associated with HSP70 can act as a unique indicator of cellular protein activity and a novel source of potential tumour biomarkers.
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Affiliation(s)
- Christina Siebke
- Moyne Institute for Preventive Medicine, School of Genetics and Microbiology, Trinity College Dublin, College Green, Dublin 2, Ireland
| | - Tharappel C. James
- Moyne Institute for Preventive Medicine, School of Genetics and Microbiology, Trinity College Dublin, College Green, Dublin 2, Ireland
| | - Robert Cummins
- Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland
| | - Tony O’Grady
- Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland
| | - Elaine Kay
- Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland
| | - Ursula Bond
- Moyne Institute for Preventive Medicine, School of Genetics and Microbiology, Trinity College Dublin, College Green, Dublin 2, Ireland
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23
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Rao R, Balusu R, Fiskus W, Mudunuru U, Venkannagari S, Chauhan L, Smith JE, Hembruff SL, Ha K, Atadja P, Bhalla KN. Combination of pan-histone deacetylase inhibitor and autophagy inhibitor exerts superior efficacy against triple-negative human breast cancer cells. Mol Cancer Ther 2012; 11:973-83. [PMID: 22367781 DOI: 10.1158/1535-7163.mct-11-0979] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Histone deacetylase (HDAC) inhibitors (HDI) induce endoplasmic reticulum (ER) stress and apoptosis, while promoting autophagy, which promotes cancer cell survival when apoptosis is compromised. Here, we determined the in vitro and in vivo activity of the combination of the pan-HDI panobinostat and the autophagy inhibitor chloroquine against human estrogen/progesterone receptor and HER2 (triple)-negative breast cancer (TNBC) cells. Treatment of MB-231 and SUM159PT cells with panobinostat disrupted the hsp90/histone deacetylase 6/HSF1/p97 complex, resulting in the upregulation of hsp. This was accompanied by the induction of enhanced autophagic flux as evidenced by increased expression of LC3B-II and the degradation of the autophagic substrate p62. Treatment with panobinostat also induced the accumulation and colocalization of p62 with LC3B-II in cytosolic foci as evidenced by immunofluorescent confocal microscopy. Inhibition of panobinostat-induced autophagic flux by chloroquine markedly induced the accumulation of polyubiquitylated proteins and p62, caused synergistic cell death of MB-231 and SUM159PT cells, and inhibited mammosphere formation in MB-231 cells, compared with treatment with each agent alone. Finally, in mouse mammary fat pad xenografts of MB-231 cells, a tumor size-dependent induction of heat shock response, ER stress and autophagy were observed. Cotreatment with panobinostat and chloroquine resulted in reduced tumor burden and increased the survival of MB-231 breast cancer xenografts. Collectively, our findings show that cotreatment with an autophagy inhibitor and pan-HDI, for example, chloroquine and panobinostat results in accumulation of toxic polyubiquitylated proteins, exerts superior inhibitory effects on TNBC cell growth, and increases the survival of TNBC xenografts.
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Affiliation(s)
- Rekha Rao
- The University of Kansas Cancer Center, Kansas City, KS 66160, USA
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Abstract
Heat shock protein 70 (Hsp70) is a powerful chaperone whose expression is induced in response to a wide variety of physiological and environmental insults, including anticancer chemotherapy, thus allowing the cell to survive to lethal conditions. Hsp70 cytoprotective properties may be explained by its anti-apoptotic function. Indeed, this protein can inhibit key effectors of the apoptotic machinery at the pre- and postmitochondrial level. In cancer cells, the expression of Hsp70 is abnormally high, and Hsp70 may participate in oncogenesis and in resistance to chemotherapy. In rodent models, Hsp70 overexpression increases tumor growth and metastatic potential. Depletion or inhibition of Hsp70 frequently reduces the size of the tumors and even can cause their complete involution. But Hsp70 can also be found in the extracellular medium. Its role is then immunogenic and the term chaperokine to define the extracellular chaperones has been advanced. Hsp70 tumorigenic functions as well as the strategies that are being developed in cancer therapy in order to inhibit Hsp70 are commented in this chapter.
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25
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Abstract
As one member of 70 kDa heat shock proteins, glucose-regulated protein 78 (GRP78) participates in protein folding, transportation and degradation. This sort of capacity can be enhanced by stresses under which GRP78 is induced rapidly. Unlike its homologues, GRP78 presents multifaceted subcellular position: When ER retention, it serves as the switch of unfolded protein response; When mitochondrial binding, it directly interacts with apoptotic executors; When cell surface residing, it recognizes extracellular ligands, transducing proliferative signals, especially in certain tumors. The close correlation between GRP78 and neoplasm provides us further insight into the event of carcinogenesis and cancer cell chemoresistance, indicating its prognostic predicting significance and validating potential therapeutics for clinical usage, especially because its small molecular inhibitors are emerging quickly these years. What's more, GRP78-related signaling may be helpful for clearer understanding of its biological mechanisms.
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Affiliation(s)
- Lu-Hua Zhang
- Neurosurgical Institute of PLA, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China
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26
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Vargas AJ, Burd R. Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutr Rev 2010; 68:418-28. [PMID: 20591109 DOI: 10.1111/j.1753-4887.2010.00301.x] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Quercetin is a unique dietary polyphenol because it can exert biphasic dose-responses on cells depending on its concentration. Cancer preventative effects of quercetin are observed at concentrations of approximately 1-40 microM and are likely mediated by quercetin's antioxidant properties. Pro-oxidant effects are present at cellular concentrations of 40-100 microM. However, at higher concentrations, many novel pathways in addition to ROS contribute to its effects. The potent bioactivity of quercetin has led to vigorous study of this compound and revealed numerous pathways that could interact synergistically to prevent or treat cancer. The effect of intake and concentration on emerging pathways and how they may interact are discussed in this review.
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Affiliation(s)
- Ashley J Vargas
- Department of Nutritional Sciences at the University of Arizona, Tucson, Arizona 85721, USA
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Park SR, Lee KD, Kim UK, Gil YG, Oh KS, Park BS, Kim GC. Pseudomonas aeruginosa exotoxin A reduces chemoresistance of oral squamous carcinoma cell via inhibition of heat shock proteins 70 (HSP70). Yonsei Med J 2010; 51:708-16. [PMID: 20635445 PMCID: PMC2908850 DOI: 10.3349/ymj.2010.51.5.708] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Revised: 12/24/2009] [Accepted: 12/24/2009] [Indexed: 12/04/2022] Open
Abstract
PURPOSE Oral squamous carcinoma (OSCC) cells exhibit resistance to chemotherapeutic agent-mediated apoptosis in the late stage of malignancy. Increased levels of heat shock proteins 70 (HSP70) in cancer cells are known to confer resistance to apoptosis. Since recent advances in the understanding of bacterial toxins have produced new strategies for the treatment of cancers, we investigated the effect of Pseudomonas aeruginosa exotoxin A (PEA) on HSP70 expression and induction of apoptosis in chemoresistant OSCC cell line (YD-9). MATERIALS AND METHODS The apoptotic effect of PEA on chemoresistant YD-9 cells was confirmed by MTT, Hoechst and TUNEL stains, DNA electrophoresis, and Western blot analysis. RESULTS While YD-9 cells showed high resistance to chemotherapeutic agents such as etoposide and 5-fluorouraci (5-FU), HSP70 antisense oligonucelotides sensitized chemoresistant YD-9 cells to etoposide and 5-FU. On the other hand, PEA significantly decreased the viability of YD-9 cells by deteriorating the HSP70-relating protecting system through inhibition of HSP70 expression and inducing apoptosis in YD-9 cells. Apoptotic manifestations were evidenced by changes in nuclear morphology, generation of DNA fragmentation, and activation of caspases. While p53, p21, and E2F-1 were upregulated, cdk2 and cyclin B were downregulated by PEA treatment, suggesting that PEA caused cell cycle arrest at the G2/M checkpoint. CONCLUSION Therefore, these results indicate that PEA reduced the chemoresistance through inhibition of HSP70 expression and also induced apoptosis in chemoresistant YD-9 cells.
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Affiliation(s)
- Sang Rye Park
- Department of Oral Anatomy, School of Dentistry, Research Institute for Oral Biotechnology, Pusan National University, Yangsan, Korea
| | - Kyoung Duk Lee
- Department of Oral Anatomy, School of Dentistry, Research Institute for Oral Biotechnology, Pusan National University, Yangsan, Korea
| | - Uk Kyu Kim
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Research Institute for Oral Biotechnology, Pusan National University, Yangsan, Korea
| | - Young Gi Gil
- Department of Anatomy, College of Medicine, Kosin University, Busan, Korea
| | - Kyu Seon Oh
- Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Bong Soo Park
- Department of Oral Anatomy, School of Dentistry, Research Institute for Oral Biotechnology, Pusan National University, Yangsan, Korea
| | - Gyoo Cheon Kim
- Department of Oral Anatomy, School of Dentistry, Research Institute for Oral Biotechnology, Pusan National University, Yangsan, Korea
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Affiliation(s)
- Christopher G. Evans
- Department of Pathology and the Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216
| | - Lyra Chang
- Department of Pathology and the Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216
| | - Jason E. Gestwicki
- Department of Pathology and the Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216
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Wang J, Yin Y, Hua H, Li M, Luo T, Xu L, Wang R, Liu D, Zhang Y, Jiang Y. Blockade of GRP78 sensitizes breast cancer cells to microtubules-interfering agents that induce the unfolded protein response. J Cell Mol Med 2009; 13:3888-97. [PMID: 19674193 PMCID: PMC4516536 DOI: 10.1111/j.1582-4934.2009.00873.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Taxane and vinblastine represent two classes of microtubules-targeted agents for cancer chemotherapy. Although taxol and vinblastine are widely used for cancer treatment, resistance to these agents is frequently encountered in the clinic. An ongoing question has been what mechanisms are involved in the resistance of tumour cells to microtubules-targeted agents or how the clinical effectiveness can be improved. There is increasing evidence that microtubules interact with the endoplasmic reticulum (ER). Here, we have shown that taxol and vinblastine induce multiple arms of the ER stress response, including up-regulation of glucose-regulated protein 78 (GRP78) expression, X-box binding protein 1 splicing and eukaryotic initiation factor 2α phosphorylation. Abrogation of GRP78 induction sensitizes breast cancer cells to taxol and vinblastine. Treatment with (-)-epigallocatechin gallate (EGCG), a known GRP78 inhibitor, synergistically promotes taxol- and vinblastine-induced cell death. GRP78 knockdown or EGCG potentiates taxol- and vinblastine-induced activation of pro-apoptosis arms of the ER stress response, such as JNK phosphorylation, caspase-7 and PARP cleavage. Inhibition of JNK and caspase-7 abrogates EGCG sensitization of breast cancer cells to taxol and vinblastine. We conclude that induction of the unfolded protein response represents a novel mechanism underlying the efficacy and resistance to microtubules-targeted agents. Combination of compounds capable of suppressing GRP78 might be a novel approach for improving the effectiveness of microtubules-targeted chemotherapy.
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Affiliation(s)
- Jiao Wang
- Division of Signal Transduction and Molecular Targeted Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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