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Bryostatin-1 inhibits cell proliferation of hepatocarcinoma and induces cell cycle arrest by activation of GSK3β

Wang, Jianfeng, Wang, Zhicheng, Sun, Yu, Liu, Dahai
Biochemical and biophysical research communications 2019 v.512 no.3 pp. 473-478
Neritina, Western blotting, aquatic organisms, carcinogenesis, cell cycle checkpoints, cell proliferation, hepatoma, in vivo studies, macrolides, mechanism of action, prospective studies, protein degradation, proteolysis, surface plasmon resonance, tau-protein kinase, therapeutics
Bryostatin-1, a macrolide lactone derived from marine organism Bugula neritina, has been shown to inhibit carcinogenesis in several prospective clinical trials. In the current study, the therapeutic potential of bryostatin-1 in inhibiting proliferation of hepatocarcinoma was evaluated by in vitro and in vivo studies. The mechanisms of action of bryostatin-1 were predicted by in silico assay and further validated by surface plasmon resonance and western blot assay. Our results show that bryostatin-1 (100, 200 nM) treatment can suppress cell proliferation and induce G1 cell cycle arrest in PLC/PRF/5 and SMCC7721 cell. We also found a significant inhibitory action of bryostatin-1 (100, 200 nM) on CyclinD1 activity in PLC/PRF/5 cells, and bryostatin-1 can promote ubiquitination-dependent protein degradation of CyclinD1 in PLC/PRF/5 cells. Western blot results confirmed that the active form phospho-GSK3β Tyr216 expression was increased significantly after bryostatin-1 treatment. Activation of GSK3β might be responsible for bryostatin-1 induced cyclinD1 degradation and cell cycle arrest. Taken together, bryostatin-1 may inhibit HCC cells proliferation by promoting cyclinD1 proteolysis and inducing cell cycle arrest.