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

Abstract

BackgroundResveratrol, 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 methodsA549 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.ResultsIn 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.ConclusionTaken 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.

The Roles of Sirtuin Family Proteins in Cancer Progression

“…Therefore, further research is needed to better understand the roles of sirtuins on anti-tumor immunity. [162,163] Inducing autophagy in lung cancer cells [164]; inducing apoptosis and upregulation of PD-L1 expression in breast and colon cancer cells [159].…”

Oxyresveratrol Induces Autophagy via the ER Stress Signaling Pathway, and Oxyresveratrol-Induced Autophagy Stimulates MUC2 Synthesis in Human Goblet Cells

“…Resveratrol and OXY upregulate autophagy via the MAPK signaling pathway. Resveratrol induces apoptosis and autophagy by inhibiting Akt/mTOR and activating the p38-MAPK pathway [41]. It is reported that resveratrol exerts neuroprotective effects by modulating mitochondrial dynamics and upregulating autophagic flux via the MEK/ERK pathway [42].…”

Sirt1 modulates H3 phosphorylation and facilitates osteosarcoma cell autophagy

“…Autophagy can offer tumor cells with a survival-promoting activity in response to the bad environment and tumor cells can activate autophagy to promote growth and aggressiveness [33]. Sirt1 is found to engage in the modulation of a number of tumor cell autophagy [34,35]. Niu et al reported that Sirt1 took part in the alisertib, an aurora kinase A inhibitor-activated osteosarcoma cell autophagy [36].…”