Chaperone-mediated autophagy promotes lung cancer cell survival through selective stabilization of the pro-survival protein, MCL1
| Autor: | Junya Suzuki, Wataru Nakajima, Yumi Asano, Hidenori Suzuki, Nobuyuki Tanaka |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Cell Survival Pyridines Biophysics Antineoplastic Agents Apoptosis Protein degradation Biology Biochemistry 03 medical and health sciences 0302 clinical medicine Chaperone-mediated autophagy Crizotinib Carcinoma Non-Small-Cell Lung Cell Line Tumor Lysosome Autophagy medicine Humans MCL1 Molecular Biology Sulfonamides Aniline Compounds Cancer Combination chemotherapy Cell Biology medicine.disease Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Proteolysis Cancer cell Cancer research Myeloid Cell Leukemia Sequence 1 Protein Pyrazoles RNA Interference Lysosomes Molecular Chaperones |
| Zdroj: | Biochemical and Biophysical Research Communications. 482:1334-1340 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2016.12.037 |
| Popis: | Autophagy is a dynamic recycling system using lysosomal proteolysis that produces new proteins and energy for cellular renovation and homeostasis. Although macroautophagy is known to serve as a survival pathway in many cancer cells, the role of chaperone-mediated autophagy (CMA), a selective protein degradation system, in cancer is not fully understood. Here, we demonstrated that lysosomal proteolysis, but not macroautophagy, attenuated apoptosis induced by the tyrosine kinase inhibitor, crizotinib, in the non-small-cell lung cancer (NSCLC) cell line, EBC1. In EBC1 cells, crizotinib induced BIM-dependent apoptosis, which was enhanced by inhibition of lysosomal proteolysis. Moreover, degradation of the pro-survival protein, MCL1, by the ubiquitin-proteasome system was induced by inhibition of lysosomal proteolysis, and by inhibition of the expression of the CMA mediators, HSC70 (heat shock cognate protein 70 kDa) and LAMP2A (lysosome membrane protein type 2A), suggesting the existence of a CMA-mediated MCL1 stabilization system in cancer cells. Indeed, the same MCL1 stabilization system was also observed in several NSCLC cell lines; in these cells, their specific molecular-targeted drug or ABT-263 (Navitoclax), the specific inhibitor of BCL-2 and BCL-XL, but not of MCL1, effectively induced apoptosis in combination with CMA inhibition. Therefore, our results indicate a novel mechanism of MCL1 stabilization in lung cancers by CMA, and a candidate efficient combination chemotherapy method against lung cancers. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect