title: The BH3-mimetic gossypol and noncytotoxic doses of valproic acid induce apoptosis by suppressing cyclin-A2/Akt/FOXO3a signaling.
abstract: 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.
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Gao-Xiang
authors.initials: GX
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Xu
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Qiu-Ru
authors.initials: QR
authors.lastname: Lin
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Mei-Yun
authors.initials: MY
authors.lastname: Huang
authors.affiliation: Department of Chemistry, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Ji-Ye
authors.initials: JY
authors.lastname: Cai
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Ouyang
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Xian-Hui
authors.initials: XH
authors.lastname: He
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056751:Cyclin A2 / Q000378:metabolism*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006072:Gossypol / Q000494:pharmacology*; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: C474007:Bax protein (53-86); D056751:Cyclin A2; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D014635:Valproic Acid; D051057:Proto-Oncogene Proteins c-akt; D006072:Gossypol
keywords: Akt; FOXO3a; apoptosis; gossypol; valproic acid