Resveratrol, an activator of SIRT1, induces protective autophagy in non-small-cell lung cancer via inhibiting Akt/mTOR and activating p38-MAPK

Background: Resveratrol, a natural polyphenolic phytoalexin, has potent anti-tumor activity. Recently, it was found to induce Autophagy in Cancer cells. However, the effects of resveratrol on Autophagy in non-small-cell lung Cancer (NSCLC) cells have not yet been clearly elucidated.

Materials and methods: A549 and H1299 cells were treated with different concentrations of resveratrol. Cell growth and Apoptosis were measured by CCK-8 assay and flow cytometry, respectively. A549 cells were then treated with 200 μM resveratrol or SRT1720. Cell Autophagy was detected by western blot and immunofluorescence.

Results: In this study, we found that resveratrol exerted the anti-tumor effect through inhibiting cell proliferation and promoting cell Apoptosis in NSCLC cells dose-dependently. Resveratrol has also increased the relative expression of Beclin1 and LC3 II/I while decreased p62 expression, suggesting that resveratrol induced Autophagy in NSCLC cells. In addition, resveratrol increased SIRT1 expression and SIRT1 Activator SRT1720-induced Autophagy of NSCLC cells. SIRT1 knockdown reduced resveratrol-induced Autophagy significantly. These results indicated that resveratrol might induce Autophagy through upregulating SIRT1 expression. Moreover, inhibiting Autophagy by Autophagy Inhibitor 3-methyladenine or SIRT1 Inhibitor nicotinamide significantly suppressed proliferation while promoted Apoptosis compared with the resveratrol 200 μM group, suggesting that resveratrol-induced Autophagy might act as a protective mechanism to promote NSCLC cell survival and inhibiting Autophagy can enhance the anti-tumor effect of resveratrol. Besides that, resveratrol treatment inhibited Akt/mTOR while p38-MAPK was activated in NSCLC cells in a dose-dependent manner. Activating Akt/ mTOR pathway by IGF-1 or inhibiting p-38-MAPK pathway by doramapimod significantly inhibited cell proliferation while increased cell Apoptosis of NSCLC cells compared with the resveratrol 200 μM group.

Conclusion: Taken together, our findings suggest that resveratrol inhibited proliferation but induced Apoptosis and Autophagy via inhibiting Akt/mTOR and activating p38-MAPK pathway. Resveratrol-induced Autophagy might act as a protective mechanism to promote NSCLC cell survival. Therefore, inhibition of Autophagy may enhance the anti-tumor activity of resveratrol in NSCLC.