Piceatannol enhances Beclin-1 activity to suppress tumor progression and its combination therapy strategy with everolimus in gastric cancer  

作　　者：Longtao Huangfu Xiaoyang Wang Shanshan Tian Junbing Chen Xueying Wang Biao Fan Qian Yao Gangjian Wang Cong Chen Jing Han Xiaofang Xing Jiafu Ji 

机构地区：[1]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education),Division of Gastrointestinal Cancer Translational Research Laboratory,Peking University Cancer Hospital&Institute,Beijing 100142,China [2]Department of Pharmacy,Peking University Cancer Hospital&Institute,Beijing 100142,China [3]National Institute on Drug Dependence,Peking University,Beijing 100191,China [4]Gastrointestinal Cancer Center,Peking University Cancer Hospital&Institute,Beijing 100142,China [5]Department of Pathology,Peking University Cancer Hospital&Institute,Beijing 100142,China

出　　处：《Science China(Life Sciences)》2023年第2期298-312,共15页中国科学（生命科学英文版）

基　　金：supported by the Natural Science Foundation of Beijing,China(7214215);the Beijing Municipal Administration of Hospitals Incubating Program(PZ2021025);the Science Foundation of Peking University Six Hospital(YJJ0008);the National Natural Science Foundation of China(82203579,81872502,81402308);the Science Foundation of Peking University Cancer Hospital(2020-23,2021-24,202126);the Clinical Medicine Plus X-Young Scholars Project(PKU2020LCXQ001);the“Double First Class”Disciplinary Development Foundation of Peking University(BMU2019LCKXJ011);The first author,Longtao Huangfu,would like to give special thanks to the Beijing Natural Science Foundation Committee for granting the first research grant。

摘　　要：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.

关 键 词：PICEATANNOL BECLIN-1 autophagy EVEROLIMUS gastric cancer drug synergy 

分 类 号：R730.2[医药卫生—肿瘤]