title: Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells.
abstract: Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α-dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation 'was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis.
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, China.
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Wu
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, China.
authors.forename: Zi-Feng
authors.initials: ZF
authors.lastname: Jiang
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, China.
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Ding
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, China.
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Shao
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, China.
authors.forename: Rong-Yu
authors.initials: RY
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D001343:Autophagy / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D002945:Cisplatin; D010100:Oxygen