Abstract
Resveratrol is a potential polyphenol drug used in cancer treatment. We examined the relationship between autophagy and apoptosis in RSV-treated non-small lung adenocarcinoma A549 cells. Resveratrol treatment increased autophagy and autophagy-mediated degradation of P62. Immunocytochemistry revealed P62 co-localized with Fas/Cav-1 complexes, known to induce apoptosis. However, siRNA-mediated P62 downregulation enhanced formation of Fas/Cav-1 complexes, suggesting that P62 inhibited Fas/Cav-1 complex formation. Fas/Cav-1 complexes triggered caspase-8 activation and cleavage of Beclin-1, releasing a C-terminal Beclin-1 peptide that translocated to the mitochondria and initiate apoptosis. Inhibition of autophagy by siRNA-mediated repression of Beclin-1 also blocked RSV-induced apoptosis, showing a dependence of apoptosis on autophagy. P62 knockdown by siRNA accelerated the activation of caspase-8 and initiate apoptosis, while Cav-1 knockdown inhibited apoptosis, but increased autophagy. Inhibition of autophagy by 3-MA prevented both P62 degradation and induction of apoptosis, whereas inhibition of apoptosis by z-IETD-FMK or z-DEVD-FMK enhanced both P62 induction and autophagic cell death. In conclusion, P62 links resveratrol-induced autophagy to apoptosis. P62 blocks apoptosis by inhibiting Fas/Cav-1 complex formation, but RSV-induced autophagic degradation of P62 enables formation of Fas/Cav-1 complexes which then activate caspase-8-mediated Beclin-1 cleavage, resulting in translocation of the Beclin-1 C-terminal fragment to the mitochondria to initiate apoptosis.
Highlights
Resveratrol, a polyphenol phytoalexin found in grapes, peanuts and other plants, is well-known for its potential antioxidant, anti-tumorigenic activities [1,2,3,4], extends lifespan by activate Sirt1 [5, 6]
To investigate the cytotoxic activity of RSV on A549 cells, exponentially growing cells were incubated with 50 μM RSV, cell viability was measured at various times following RSV addition (Fig. 1A)
The results demonstrated that RSV induced apoptosis 48 h after treatment with RSV, which was strongly reduced by Z-DEVD-FMK, whereas RSV-induced autophagy was evident by 12 h, increased up to 24 h, dramatically dropped to low levels by 48 h
Summary
Resveratrol (trans 3, 4’, 5-trihydroxystilbene; RSV), a polyphenol phytoalexin found in grapes, peanuts and other plants, is well-known for its potential antioxidant, anti-tumorigenic activities [1,2,3,4], extends lifespan by activate Sirt1 [5, 6]. Accumulated reports demonstrate that RSV has the ability to affect tumor initiation and promotion, arrest angiogenesis and metastasis, and induce cell cycle arrest and apoptosis [7]. Previous studies have indicated that resveratrol inhibits the proliferation of A549 non-small adenocarcinoma cells and induces apoptosis [8]. Studies on autophagy induced by resveratrol in A549 cells have attracted an immense amount of attention for its potential antitumor activity [9]. RSV is currently in phase I clinical development with preliminary evidence of antitumor activity [10]. The actual mechanisms of RSV-induced cell death and the specific molecular targets of RSV in A549 cancer cells have not yet fully established
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