The BH3-mimetic gossypol and noncytotoxic doses of valproic acid induce apoptosis by suppressing cyclin-A2/Akt/FOXO3a signaling
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Gao-Xiang Zhao1,*, Li-Hui Xu2,*, Hao Pan1, Qiu-Ru Lin1, Mei-Yun Huang1, Ji-Ye Cai3, Dong-Yun Ouyang1, Xian-Hui He1
1Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China
2Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
3Department of Chemistry, College of Life Science and Technology, Jinan University, Guangzhou, China
*These authors have contributed equally to this work
Xian-Hui He, e-mail: [email protected]
Dong-Yun Ouyang, e-mail: [email protected]
Keywords: gossypol, valproic acid, apoptosis, akt, FOXO3a
Received: April 29, 2015 Accepted: October 06, 2015 Published: October 16, 2015
Previously we reported that valproic acid (VPA) acts in synergy with GOS to enhance cell death in human DU145 cells. However, the underlying mechanism remains elusive. In this study, we observed that such synergistic cytotoxicity of GOS and VPA could be extended to human A375, HeLa, and PC-3 cancer cells. GOS and VPA co-treatment induced robust apoptosis as evidenced by caspase-8/-9/-3 activation, PARP cleavage, and nuclear fragmentation. GOS and VPA also markedly decreased cyclin A2 protein expression. Owing to the reduction of cyclin A2, Akt signaling was suppressed, leading to dephosphorylation of FOXO3a. Consequently, FOXO3a was activated and the expression of its target genes, including pro-apoptotic FasL and Bim, was upregulated. Supporting this, FOXO3a knockdown attenuated FasL and Bim upregulation and apoptosis induction in GOS+VPA-treated cells. Furthermore, blocking proteasome activity by MG132 prevented the downregulation of cyclin A2, dephosphorylation of Akt and FOXO3a, and induction of apoptosis in cells co-treated with GOS and VPA. In mouse model, GOS and VPA combination significantly inhibited the growth of A375 melanoma xenografts. Our findings indicate that GOS and VPA co-treatment induces apoptosis in human cancer cells by suppressing the cyclin-A2/Akt/FOXO3a pathway.
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