Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells.
Autophagy defect has been shown to be correlated with malignant phenotype and poor prognosis of human cancers, however, the detailed mechanisms remain obscure. In this study, we investigated the biological changes induced by autophagy inhibition in gastric cancer. We showed that inhibition of autophagy in gastric cancer cells promotes epithelial-mesenchymal transition (EMT) and metastasis, alters metabolic phenotype from mitochondrial oxidative phosphorylation to aerobic glycolysis and converts cell phenotype toward malignant, which maybe further contribute to chemoresistance and poor prognosis of gastric cancer. We also identified that the EMT and metabolism alterations induced by autophagy inhibition were dependent on ROS-NF-κB-HIF-1α pathway. More importantly, scavenging of ROS by the antioxidant N-acetylcysteine (NAC) attenuated activation of NF-κB and HIF-1α in autophagy-deficient gastric cancer cells, and autophagy inhibition induced metastasis and glycolysis were also diminished by NAC in vivo. Taken together, our findings suggested that autophagy defect promotes metastasis and glycolysis of gastric cancer, and antioxidants could be used to improve disease outcome for gastric cancer patients with autophagy defect.
Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
Wenjie
W
Qin
Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
Chao
C
Li
Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
Wen
W
Zheng
Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
Qingqu
Q
Guo
Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
Yuefeng
Y
Zhang
Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
Muxing
M
Kang
Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
Bo
B
Zhang
Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
Bin
B
Yang
Department of Oncosurgery, Anyang Tumor Hospital, Henan, P. R. China.
Baozhong
B
Li
Department of Pathology, Anyang Tumor Hospital, Henan, P. R. China.
Haijun
H
Yang
Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.|Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
Yulian
Y
Wu
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D000071186:Beclin-1; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D016166:Free Radical Scavengers; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D034622:RNA Interference; D000067492:RNAi Therapeutics / Q000379:methods; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D016166:Free Radical Scavengers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D000111:Acetylcysteine
antioxidant; autophagy inhibition; glycolysis; metastasis; reactive oxygen species (ROS)