Abstract
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.
Highlights
Gastric cancer is the second deadliest disease among cancers worldwide and the incidence rate is highest in Eastern Asia [1,2,3]
Our results indicated that autophagy provides metabolic intermediates for mitochondrial oxidative phosphorylation to fuel cell survival, while autophagy defect causes the shift from oxidative phosphorylation to aerobic glycolysis for proper energy homeostasis in gastric cancer cells
In the 1920s, Otto Warburg put forward the claim that the energy supply of cancer cells mainly rely on aerobic glycolysis, which is in contrast to normal cells [22]
Summary
Gastric cancer is the second deadliest disease among cancers worldwide and the incidence rate is highest in Eastern Asia [1,2,3]. It’s urgent to explore for more effective treatment options. Due to the heterogeneity of gastric cancer, there are individual differences in tumor aggressiveness, histopathologic features, and treatment response [5]. Autophagy is a dynamic catabolic process to maintain intracellular homeostasis. Autophagy degrades intracellular damaged proteins and organelles and converts them to metabolic intermediates in the autolysosomes for energy generation and biosynthesis [6, 7]. Autophagy can support tumor cells survival through generating substrates for mitochondrial metabolism, preventing metabolic stress, mitigating accumulation of toxic substances and so on [7, 8]. Defective autophagy is involved in the onset and progression of tumors via inducing inflammation and necrosis [9,10,11]. The role of autophagy in tumors is complicated and further investigation is needed to elucidate the character of autophagy
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