Cisplatin modulates B-cell translocation gene 2 to attenuate cell proliferation of prostate carcinoma cells in both p53-dependent and p53-independent pathways.

Kun-Chun Chiang,Wen-Tsung Chen,Hou-Yu Chiang,Ke-Hung Tsui,Phei-Lang Chang,Tsui-Hsia Feng,Li-Chuan Chung,Horng-Heng Juang,Chun-Nan Yeh

doi:10.1038/srep05511

Abstract

Cisplatin is a widely used anti-cancer drug. The B-cell translocation gene 2 (BTG2) is involved in the cell cycle transition regulation. We evaluated the cisplatin effects on prostate cancer cell proliferation and the expressions of BTG2, p53, androgen receptor (AR) and prostate specific antigen (PSA) in prostate carcinoma, p53 wild-type LNCaP or p53-null PC-3, cells. Cisplatin treatments attenuated cell prostate cancer cell growth through inducing Go/G1 cell cycle arrest in lower concentration and apoptosis at higher dosage. Cisplatin treatments enhanced p53 and BTG2 expression, repressed AR and PSA expression, and blocked the activation of androgen on the PSA secretion in LNCaP cells. BTG2 knockdown in LNCaP cells attenuated cisplatin-mediated growth inhibition. Cisplatin enhanced BTG2 gene expression dependent on the DNA fragment located within -173 to -82 upstream of BTG2 translation initiation site in prostate cancer cells. Mutation of the p53 response element from GGGCAGAGCCC to GGGCACC or mutation of the NFκB response element from GGAAAGTCC to GGAAAGGAA by site-directed mutagenesis abolished the stimulation of cisplatin on the BTG2 promoter activity in LNCaP or PC-3 cells, respectively. Our results indicated that cisplatin attenuates prostate cancer cell proliferation partly mediated by upregulation of BTG2 through the p53-dependent pathway or p53-independent NFκB pathway.

Highlights

Cisplatin modulates B-cell translocation gene 2 to attenuate cell proliferation of prostate carcinoma cells in both p53-dependent and p53-independent pathways
Our results indicated LNCaP cell proliferation was inhibited by 24 hours of cisplatin treatment in a dose-dependent manner, with 41% and 50% decreases noted when treated with 40 and 80 mM cisplatin, respectively. 48 hours cisplatin treatment clearly showed more prominent cell proliferation inhibition in LNCaP cells under the concentrations from 5 to 80 mM
Since 80 mM of cisplatin increased the sub-G1 fraction of cells by 7–10%, it clearly indicated high dose of cisplatin was able to induced LNCaP cell apoptosis (Figure 1b). This is supported by the immunoblot assay revealing that treatment with 80 mM of cisplatin induced the expression of cleaved form of PARP in LNCaP cells (Figure 1c)

Summary

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We evaluated the cisplatin effects on prostate cancer cell proliferation and the expressions of BTG2, p53, androgen receptor (AR) and prostate specific antigen (PSA) in prostate carcinoma, p53 wild-type LNCaP or p53-null PC-3, cells. Cisplatin enhanced BTG2 gene expression dependent on the DNA fragment located within -173 to -82 upstream of BTG2 translation initiation site in prostate cancer cells. Our results indicated that cisplatin attenuates prostate cancer cell proliferation partly mediated by upregulation of BTG2 through the p53-dependent pathway or p53-independent NFkB pathway. Our previous study has shown that topoisomerase inhibitors could repress prostate cancer cell growth and induce BTG2 expressions in a p53 dependent manner[14]. Our objectives for this study are to determine the effects of cisplatin on prostate cancer cell growth, the AR and PSA expression, as well as the regulatory mechanisms of cisplatin on the gene expression of BTG2 in prostate cancer cells

Results

Discussion

Methods

Additional information

Author contributions