Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway

• Published in: Drug design, development and therapy Vol. 9; no. Issue 1; pp. 6421 - 6431
• Main Authors: Wu, Tao, Wang, Min-Cong, Jing, Li, Liu, Zhi-Yan, Guo, Hui, Liu, Ying, Bai, Yi-Yang, Cheng, Yang-Zi, Nan, Ke-Jun, Liang, Xuan
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2015; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma of Lung; AMP-Activated Protein Kinases - metabolism; AMPK/mTOR; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Autophagy; Autophagy (Cytology); Autophagy - drug effects; Cancer therapies; Cell growth; Cell Proliferation - drug effects; Cell Survival - drug effects; Cellular signal transduction; Chemotherapy; Chloroquine; chlororquine; Cisplatin; Cisplatin - chemistry; Cisplatin - pharmacology; cisplatin-resistance; Development and progression; Dose-Response Relationship, Drug; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Genetic aspects; Genotype; Health aspects; Homology; Hospitals; Humans; Identification and classification; Immunoglobulins; Kinases; Localization; lung adenocarcinoma; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Metabolism; Molecular modelling; Original Research; Phagocytosis; Proteins; Signal transduction; Signal Transduction - drug effects; Signaling; Structure-Activity Relationship; Substance abuse treatment; Therapeutic applications; Therapy; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor Cells, Cultured; Yeast; United States > US; China; A549/DDP cells; chloroquine; lung cancer; chemoresistance; autophagy; A549 cells; AMPK
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/dddt.s95606

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.