title: Chaperone-mediated autophagy promotes lung cancer cell survival through selective stabilization of the pro-survival protein, MCL1.
abstract: 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.
authors.affiliation: Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nakajima
authors.affiliation: Division of Morphological and Biomolecular Research, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan. Electronic address: nobuta@nms.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D001343:Autophagy; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D000077547:Crizotinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D059748:Proteolysis; D011720:Pyrazoles / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D034622:RNA Interference; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D018832:Molecular Chaperones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D000077547:Crizotinib; C528561:navitoclax
keywords: Apoptosis; Cancer chemotherapy; Chaperone-mediated autophagy; Lung cancer; MCL1; Ubiquitination