Gastric cancer (GC) is often diagnosed in the advanced stages with a poor prognosis. Thymoquinone (TQ) is known for its antitumor activity; however, the specific mechanism in GC remains unknown. In our study, TQ inhibited GC cell proliferation and induced apoptosis and autophagy in a concentration-dependent manner. Transmission electron microscopy showed increased autophagosome formation in GC cells treated with TQ. Meanwhile, the LC3B puncta and LC3BII protein levels were significantly increased in GC cells, while p62 expression was significantly decreased. The autophagy inhibitor, Bafilomycin A1 enhanced TQ-inhibited proliferation and TQ-induced apoptosis, suggesting that TQ-induced autophagy has a protective effect on GC cells. Furthermore, TQ decreased the phosphorylation levels of phosphatidylinositol-4,5-bisphosphate 3 kinase (PI3K), protein kinase B (Akt), and mechanistic target of rapamycin (mTOR). The PI3K agonist partially rescued TQ-induced autophagy and apoptosis. Finally, in vivo experiments showed that TQ could inhibit tumor growth and promote apoptosis and autophagy. This study provides new insights into the specific mechanism for the anti-GC effect of TQ. TQ inhibits the proliferation of GC cells and induces apoptosis and protective autophagy by inhibiting the PI3K/Akt/mTOR pathway. The results suggest that the combination of TQ and autophagy inhibitors might be a potential chemotherapeutic strategy for GC.
Keywords: PI3K/Akt/mTOR; apoptosis; autophagy; gastric cancer; thymoquinone.
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