Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells.
Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells.
复制标题
抑制自噬通过诱导胃癌细胞中的ROS促进转移和糖酵解。
DOI：
10.18632/oncotarget.5674
复制
发表时间：
2015-11-24
期刊：
影响因子：
--
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Qin W;Li C;Zheng W;Guo Q;Zhang Y;Kang M;Zhang B;Yang B;Li B;Yang H;Wu Y
自噬缺陷与肿瘤的恶性表型和预后不良有关，但其具体机制尚不清楚。在这项研究中，我们研究了自噬抑制诱导的胃癌生物学变化。我们发现抑制胃癌细胞自噬可促进上皮-间质转化（EMT）和转移，改变线粒体氧化磷酸化代谢表型为有氧糖酵解代谢表型，并使细胞表型向恶性转化，这可能进一步导致胃癌的化疗耐药和预后不良。自噬抑制引起的EMT和代谢改变依赖于ROS-NF-κB-HIF-1α通路。更重要的是，抗氧化剂N-乙酰半胱氨酸（NAC）清除ROS后，自噬缺陷的胃癌细胞中NF-κB和HIF-1α的活化减弱，体内自噬抑制诱导的转移和糖酵解也减弱。综上所述，我们的研究结果表明，自噬缺陷促进胃癌的转移和糖酵解，抗氧化剂可以用于改善自噬缺陷的胃癌患者的疾病结局。
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.