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PLoS One. 2014 Feb 20;9(2):e89117. doi: 10.1371/journal.pone.0089117. eCollection 2014.

Topoisomerase inhibitors modulate gene expression of B-cell translocation gene 2 and prostate specific antigen in prostate carcinoma cells.

Author information

1
Department of General Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC.
2
Department of Urology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan, ROC ; Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
3
Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
4
Department of General Surgery, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
5
National Kaohsiung University of Hospitality and Tourism, Hsiao-Kang, Kaohsiung Taiwan, ROC.

Abstract

Camptothecin (CPT) and doxorubicin (DOX) have been demonstrated to have potent anti-tumor activity. The B-cell translocation gene 2 (BTG2) is involved in the regulation of cell cycle progression. We evaluated the molecular mechanisms of CPT and DOX on cell proliferation and the expressions of BTG2 and prostate specific antigen (PSA) in prostate carcinoma cells. Our results indicated that CPT or DOX treatments induced Go/G1 cell cycle arrest in LNCaP cells and apoptosis at higher dosage. Immunoblot and transient gene expression assay indicated that CPT or DOX treatments induced p53 and BTG2 gene expression, with the later effect dependent on the p53 response element within BTG2 promoter area since mutation of the p53 response element from GGGAAAGTCC to GGAGTCC or from GGCAGAGCCC to GGCACC by site-directed mutagenesis abolished the stimulation of CPT or DOX on the BTG2 promoter activity, which is also supported by our results that cotreatments of pifithrin-α, an inhibitor of p53 dependent transcriptional activation, blocked the induction of CPT or DOX on BTG2 gene expression. CPT or DOX also downregulated the protein expressions of androgen receptor (AR) and PSA. Transient gene expression assays suggested that CPT or DOX's attenuation of PSA promoter activity is dependent on both the androgen and p53 response elements within of the PSA promoter. Our results indicated that CPT and DOX attenuate cell proliferation via upregulation of BTG2 gene expression through the p53-dependent pathway. The CPT and DOX block the PSA gene expression by upregulation of p53 activity and downregulation of androgen receptor activity.

PMID:
24586533
PMCID:
PMC3930641
DOI:
10.1371/journal.pone.0089117
[Indexed for MEDLINE]
Free PMC Article
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