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Suppression of prostate tumor cell growth in vivo by WT1, the Wilms' tumor suppressor gene.

Abstract：

:The primary form of therapy for prostate cancer is androgen ablation resulting in apoptosis and expression of apoptotic genes (i.e. par-4). Prostate cancer cells that survive androgen ablation therapy express pro-survival genes (i.e. bcl-2) permitting these androgen independent (AI) cells to overcome apoptotic signals and proliferate in the absence of normal growth signals. To disrupt tumor growth and progression to AI, we expressed the tumor suppressor gene, WT1 in LNCaP prostate tumor cells. The WT1 transcription factor modulates expression and activity of several prostate growth control genes (i.e. par-4, bcl-2 and AR) in vitro. To provide insight into potential mechanisms of prostate cancer growth suppression both the transcriptionally active form of wild-type WT1 (D) and an inactive WT1 (D) R394W mutant form were stably transfected in LNCaP cells. Surprisingly both transfected lines underwent apoptosis and were growth suppressed in nude mice. A 3-fold reduction in overall tumor incidence and volume was associated with increased apoptosis, as evidenced by DNA fragmentation and par-4 expression, and was reduced or absent in early forming LNCaP tumors. After several months the indolent WT1-LNCaP cells became proliferative forming small tumors lacking par-4 protein. Although bcl-2 protein was present in all LNCaP tumors at this late-stage, it was detected in only a minority of WT1-LNCaP tumors, suggesting that pro-survival signals continued to be reduced in WT1-suppressed tumor cells. While the mechanisms of WT1-mediated growth suppression and apoptosis in LNCaP tumor cells are unknown, our results argue against simple transcriptional regulation since the mutant WT1 (D) R394W suppressed tumor formation similarly to wild-type WT1. This suggests that the mechanism of WT1-mediated growth suppression does not rely upon DNA binding at known WT1 recognition sites.

journal_name

Int J Oncol

journal_title

International journal of oncology

authors

Fraizer G,Leahy R,Priyadarshini S,Graham K,Delacerda J,Diaz M

keywords:

subject

Has Abstract

pub_date

2004-03-01 00:00:00

pages

461-71

issue

eissn

1019-6439

issn

1791-2423

journal_volume

pub_type

杂志文章

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Suppression of prostate tumor cell growth in vivo by WT1, the Wilms' tumor suppressor gene.