Research Papers:

The BH3-mimetic gossypol and noncytotoxic doses of valproic acid induce apoptosis by suppressing cyclin-A2/Akt/FOXO3a signaling

Gao-Xiang Zhao _, Li-Hui Xu, Hao Pan, Qiu-Ru Lin, Mei-Yun Huang, Ji-Ye Cai, Dong-Yun Ouyang and Xian-Hui He

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Oncotarget. 2015; 6:38952-38966. https://doi.org/10.18632/oncotarget.5731

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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

Correspondence to:

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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