title: Inhibition of autophagy enhances heat-induced apoptosis in human non-small cell lung cancer cells through ER stress pathways.
abstract: The occurrence and mechanisms of autophagy induced by heat stress are not well known in lung cancer cells. Here, we have demonstrated that heat stress induces autophagy in A549 and NCI-H460 cells through morphological and biochemical analyses. The inhibition of autophagy by chloroquine, 3-methyladenine and Beclin 1 siRNA enhanced heat-induced apoptosis. Moreover, the combination of chloroquine and heat stress inhibited tumor growth and enhanced apoptosis in vivo experiments. In addition, heat-induced autophagy involved the ER stress pathway (PERK- or IRE1-dependent). Further, heat treatment led to the increased phosphorylation of AMPK and the decreased phosphorylation of mTOR in vitro and in vivo. Knockdown of GRP78 inhibited the AMPK-mTOR pathway, and the AMPK inhibitor compound C decreased heat-induced autophagy, suggesting that activation of ER stress was involved in autophagy induction and promotion of the AMPK-mTOR pathway. In conclusion, our data suggested that the heat treatment of lung cancer cells triggered protective autophagy, as mediated by ER stress. Thus, inhibition of autophagy can be a promising strategy to enhance hyperthermia in the treatment of lung cancer patients.
authors: Department of Oncology, Second Affiliated Hospital, Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing 400010, China. Electronic address: xiewy112@sina.com.
authors: Wen-Yue
authors: WY
authors: Xie
authors: Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing 400010, China; Division of Respiratory Medicine, Affiliated Hospital of Hainan Medical University, Haikou, China.
authors: Xiang-Dong
authors: XD
authors: Zhou
authors: Division of Respiratory Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing Academy of Traditional Chinese Medicine, Chongqing 400010, China.
authors: Juan
authors: J
authors: Yang
authors: Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing 400010, China.
authors: Ling-Xiu
authors: LX
authors: Chen
authors: Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, No.74, Linjiang Road, Yuzhong District, Chongqing 400010, China.
authors: Dan-Hua
authors: DH
authors: Ran
mesh_terms: D000072283:A549 Cells; D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1 / Q000737:chemistry; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005434:Flow Cytometry; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000737:chemistry
chemical_list: D000071186:Beclin-1; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D034741:RNA, Small Interfering; C025946:3-methyladenine; D002738:Chloroquine; D000225:Adenine
keywords: Apoptosis; Autophagy; ER stress; Heat stress; Lung cancer