PMID- 14767530
OWN - NLM
STAT- MEDLINE
DCOM- 20041025
LR  - 20061115
IS  - 1019-6439 (Print)
IS  - 1019-6439 (Linking)
VI  - 24
IP  - 3
DP  - 2004 Mar
TI  - Suppression of prostate tumor cell growth in vivo by WT1, the Wilms' tumor 
      suppressor gene.
PG  - 461-71
AB  - 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.
FAU - Fraizer, Gail
AU  - Fraizer G
AD  - Department of Biological Sciences, Kent State University, Kent, OH 44242, USA. 
      gfraizer@kent.edu
FAU - Leahy, Rachel
AU  - Leahy R
FAU - Priyadarshini, Subhadra
AU  - Priyadarshini S
FAU - Graham, Kylie
AU  - Graham K
FAU - Delacerda, Jorge
AU  - Delacerda J
FAU - Diaz, Miguel
AU  - Diaz M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Receptors, Androgen)
RN  - 0 (WT1 Proteins)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Blotting, Western
MH  - Cell Division
MH  - Cell Line, Tumor
MH  - DNA Fragmentation
MH  - *Genes, Tumor Suppressor
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Nick-End Labeling
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Microscopy, Fluorescence
MH  - Neoplasm Transplantation
MH  - Plasmids/metabolism
MH  - Prostatic Neoplasms/genetics/*metabolism/therapy
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Receptors, Androgen/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Time Factors
MH  - Transcription, Genetic
MH  - Transfection
MH  - WT1 Proteins/*biosynthesis/genetics
EDAT- 2004/02/10 05:00
MHDA- 2004/10/27 09:00
CRDT- 2004/02/10 05:00
PHST- 2004/02/10 05:00 [pubmed]
PHST- 2004/10/27 09:00 [medline]
PHST- 2004/02/10 05:00 [entrez]
PST - ppublish
SO  - Int J Oncol. 2004 Mar;24(3):461-71.