The effects and regulation of Beclin-1-an
autophagy-related protein-have not been fully defined, however, a negative correlation has been reported between
Beclin-1 expression and
carcinogenesis. Meanwhile, no compound has been shown to directly inhibit its activity. Here, we evaluate
piceatannol, a naturally occurring polyphenolic compound, as a potential targeting agonist of
Beclin-1, to assess its efficacy as an
antitumor agent against
gastric cancer. More specifically, we determine the effects of
piceatannol treatment on cell viability using a monitoring system and colony forming assay.
Piceatannol was found to efficiently inhibit the proliferation of several human
gastric cancer cell lines. Autophagic flux is increased by
piceatannol treatment, and correlates with inhibition of cell proliferation and colony formation. Additionally, microscale thermophoresis and surface plasmon resonance results show a direct interaction between
piceatannol and
Beclin-1, which reduces the phosphorylation activity of
Beclin-1 at the Ser-295 site. Notably,
piceatannol impairs the binding of
Beclin-1 to Bcl-2 and enhances the recruitment of binding of UV radiation resistance-associated gene
protein, which further triggers Beclin-1-dependent autophagy signaling. An increase in autophagic activity via treatment with the mTOR inhibitor,
everolimus, effectively sensitizes
piceatannol-induced antitumor effects. Xenograft models confirmed that
piceatannol inhibits
tumor development and elicits a potent synergistic effect with
everolimus in vivo. Taken together, the findings of this study strongly support the application of combinatorial
piceatannol and
everolimus therapy in future clinical trials for
gastric cancer patients.