Heat Shock Protein 70 (Hsp70) Suppresses RIP1-Dependent Apoptotic and Necroptotic Cascades
| Autor: | Min Zhuang, Sharan R. Srinivasan, Colin S. Duckett, Laura C. Cesa, Xiaokai Li, James A. Wells, Ivan Maillard, Jason E. Gestwicki, Olivier Julien, Jooho Chung, Hao Shao |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Necroptosis 1.1 Normal biological development and functioning Oncology and Carcinogenesis Breast Neoplasms Apoptosis Protein degradation Article CFLAR Cell Line 03 medical and health sciences RIPK1 Jurkat Cells Necrosis 0302 clinical medicine Underpinning research Heat shock protein Cell Line Tumor Breast Cancer Humans 2.1 Biological and endogenous factors HSP70 Heat-Shock Proteins Oncology & Carcinogenesis Aetiology Molecular Biology Cancer Tumor biology Hsp90 Cell biology XIAP 030104 developmental biology Oncology 030220 oncology & carcinogenesis Receptor-Interacting Protein Serine-Threonine Kinases Cancer research biology.protein MCF-7 Cells Female Signal Transduction Developmental Biology |
| Zdroj: | Molecular cancer research : MCR, vol 16, iss 1 |
| Popis: | Hsp70 is a molecular chaperone that binds to “client” proteins and protects them from protein degradation. Hsp70 is essential for the survival of many cancer cells, but it is not yet clear which of its clients are involved. Using structurally distinct chemical inhibitors, we found that many of the well-known clients of the related chaperone, Hsp90, are not strikingly responsive to Hsp70 inhibition. Rather, Hsp70 appeared to be important for the stability of the RIP1 (RIPK1) regulators: cIAP1/2 (BIRC1 and BIRC3), XIAP, and cFLIPS/L (CFLAR). These results suggest that Hsp70 limits apoptosis and necroptosis pathways downstream of RIP1. Consistent with this model, MDA-MB-231 breast cancer cells treated with Hsp70 inhibitors underwent apoptosis, while cotreatment with z-VAD.fmk switched the cell death pathway to necroptosis. In addition, cell death in response to Hsp70 inhibitors was strongly suppressed by RIP1 knockdown or inhibitors. Thus, these data indicate that Hsp70 plays a previously unrecognized and important role in suppressing RIP1 activity. Implications: These findings clarify the role of Hsp70 in prosurvival signaling and suggest IAPs as potential new biomarkers for Hsp70 inhibition. Mol Cancer Res; 16(1); 58–68. ©2017 AACR. |
| Databáze: | OpenAIRE |
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