TY - JOUR
T1 - Valproic acid synergistically enhances the cytotoxicity of gossypol in DU145 prostate cancer cells
T2 - An iTRTAQ-based quantitative proteomic analysis
AU - Ouyang, Dong Yun
AU - Ji, Yu Hua
AU - Saltis, Mark
AU - Xu, Li Hui
AU - Zhang, Yan Ting
AU - Zha, Qing Bing
AU - Cai, Ji Ye
AU - He, Xian Hui
N1 - Funding Information:
This work was supported by the Fundamental Research Funds for the Central Universities (No. 21609403 ) and grants from the Major State Basic Research Development Program of China (973 Program) (No. 2010CB833603 ), as well as the Specialized Research Program of “Twelfth Five-Year Plan” of China ( 2011ZX09307-303-03 ).
PY - 2011/9/6
Y1 - 2011/9/6
N2 - Gossypol (GOS), a BH3 mimetic, has been investigated as a sensitizing co-therapy to radiation and chemotherapy in treatment of metastatic prostate cancer. In this study, we found that valproic acid (VPA), a histone deacetylase inhibitor (HDACI), counteracted the suppressive effect of GOS on histone H3 acetylation and enhanced the cytotoxicity of GOS to DU145 prostate cancer cells. Significant synergistic effects were observed in combined GOS and VPA treatment, culminating in more DNA damage and cell death. The iTRAQ-based quantitative proteomic analysis revealed differential proteomic profiles in cells treated with VPA, GOS or their combination. In GOS-treated cells, oxidative phosphorylation-related proteins were depressed and endoplasmic reticulum stress markers were upregulated. In the presence of VPA, the GOS-induced mitochondrial stress was further enhanced since glycolysis- and hypoxia-associated proteins were upregulated, suggesting a disruption of energy metabolism in these cells. Furthermore, the DNA damage repair ability of cells co-treated with GOS and VPA was also decreased, as evidenced by the downregulation of DNA damage repair proteins and the enhancement of DNA fragmentation and cell death. These findings suggest that GOS in combination with an HDACI has the potential to increase its clinical efficacy in the treatment of prostate cancer.
AB - Gossypol (GOS), a BH3 mimetic, has been investigated as a sensitizing co-therapy to radiation and chemotherapy in treatment of metastatic prostate cancer. In this study, we found that valproic acid (VPA), a histone deacetylase inhibitor (HDACI), counteracted the suppressive effect of GOS on histone H3 acetylation and enhanced the cytotoxicity of GOS to DU145 prostate cancer cells. Significant synergistic effects were observed in combined GOS and VPA treatment, culminating in more DNA damage and cell death. The iTRAQ-based quantitative proteomic analysis revealed differential proteomic profiles in cells treated with VPA, GOS or their combination. In GOS-treated cells, oxidative phosphorylation-related proteins were depressed and endoplasmic reticulum stress markers were upregulated. In the presence of VPA, the GOS-induced mitochondrial stress was further enhanced since glycolysis- and hypoxia-associated proteins were upregulated, suggesting a disruption of energy metabolism in these cells. Furthermore, the DNA damage repair ability of cells co-treated with GOS and VPA was also decreased, as evidenced by the downregulation of DNA damage repair proteins and the enhancement of DNA fragmentation and cell death. These findings suggest that GOS in combination with an HDACI has the potential to increase its clinical efficacy in the treatment of prostate cancer.
KW - DNA damage
KW - Gossypol
KW - Prostate cancer
KW - Synergistic activity
KW - Valproic acid
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U2 - 10.1016/j.jprot.2011.06.016
DO - 10.1016/j.jprot.2011.06.016
M3 - Article
C2 - 21726675
AN - SCOPUS:80052035259
SN - 1874-3919
VL - 74
SP - 2180
EP - 2193
JO - Journal of Proteomics
JF - Journal of Proteomics
IS - 10
ER -