title: Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway.
abstract: Resistance to cisplatin-based therapy is a major challenge in the control of lung cancer progression. However, the underlying mechanisms remain largely unclear. Autophagy is closely associated with resistance to lung cancer therapy, but the function of autophagy in cisplatin treatment is still controversial. Here, we investigated whether autophagy was involved in lung adenocarcinoma resistance to cisplatin and further elucidated the underlying molecular mechanisms. Cisplatin-refractory lung adenocarcinoma cells increased autophagic vacuole formation detected by monodansylcadaverine staining. When exposed to cisplatin, lung adeno-carcinoma cells demonstrated increased levels of autophagy detected by MAP1A/1B LC3B and mammalian homologue of yeast Atg6 (Beclin-1) expression using Western blot analysis. Activation of cisplatin-induced autophagic flux was increased by using chloroquine (CQ), which can accumulate LC3B-II protein and increase punctate distribution of LC3B localization. The combination of cisplatin with CQ was more potent than cisplatin alone in inhibiting lung adenocarcinoma cell growth, which also increased cisplatin-induced apoptosis. Compared to cisplatin treatment alone, the combination of cisplatin and CQ decreased p-AMPK and increased p-mTOR protein expressions, in addition, the AMPK inhibitor Compound C plus cisplatin downregulated p-AMPK and upregulated p-mTOR as well as depressed LC3B cleavage. These findings demonstrate that activation of autophagy is a hallmark of cisplatin exposure in human lung adenocarcinoma cells, and that there is a cisplatin-induced autophagic response via activation of the AMPK/mTOR signaling pathway. We speculate that autophagy can be used as a novel therapeutic target to overcome cisplatin-resistant lung adenocarcinoma.
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Min-Cong
authors.initials: MC
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Jing
authors.affiliation: Department of Respiratory Medicine, Xi'an Central Hospital, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Zhi-Yan
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Yi-Yang
authors.initials: YY
authors.lastname: Bai
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Yang-Zi
authors.initials: YZ
authors.lastname: Cheng
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Ke-Jun
authors.initials: KJ
authors.lastname: Nan
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D002945:Cisplatin
keywords: A549 cells; A549/DDP cells; AMPK; autophagy; chemoresistance; chloroquine; lung cancer