Inhibition of transcription factor Stat5 induces cell death of human prostate cancer cells.
Identifying regulators of prostate cancer cell survival may lead to new therapeutic strategies for prostate cancer. We now report prevalent activation of transcription factor Stat5 in human prostate cancer and provide novel evidence that blocking activation of Stat5 in human prostate cancer cells leads to extensive cell death. Specifically, Stat5 was activated in 65% of human prostate cancer specimens examined based on nuclear location of tyrosine phosphorylated Stat5. Adenoviral gene delivery of a dominant-negative Stat5 mutant (DNStat5), but not wild-type Stat5, induced cell death of both the androgen-independent human prostate cancer cell line CWR22Rv and the androgen-sensitive LnCap cell line. Endogenous Stat5 was active in both CWR22Rv and LnCap cells. In contrast, only low levels of inactive Stat5 proteins were detected in the PC-3 cell line, which correlated with resistance to DNStat5-induced cell death. In CWR22Rv and LnCap cells, inhibition of Stat5 by expression of DNStat5 induced apoptotic cell death as judged from morphological changes, DNA fragmentation, and caspase-3 activation with evidence of a caspase-9-dependent mechanism. We propose that blocking Stat5 function may represent a novel therapeutic approach for prostate cancer.
Department of Oncology, Vincent T. Lombardi Cancer Center, Georgetown University Medical Center, Washington D. C. 20057, USA.
Tommi J
TJ
Ahonen
Jianwu
J
Xie
Matthew J
MJ
LeBaron
Jianqiong
J
Zhu
Martti
M
Nurmi
Kalle
K
Alanen
Hallgeir
H
Rui
Marja T
MT
Nevalainen
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004247:DNA / Q000235:genetics; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008894:Milk Proteins; D016296:Mutagenesis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D004247:DNA; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases