Inhibition of Transcription Factor Stat5 Induces Cell Death of Human Prostate Cancer Cells

Abstract

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.Prostate cancer typically progresses to androgen-independent growth after androgen-ablation therapy. Identification of androgen-independent proteins that control prostate cancer cell survival may lead to more effective therapies. Using long term organ cultures of human and rat prostate tissues, we have documented direct effects of prolactin (Prl) 1 as a mitogen and survival factor for prostate epithelium (1-4). These observations have been complemented by demonstration of massive hyperplasia of prostates in transgenic mice overexpressing Prl (5, 6) as well as reduced prostate sizes in Prl-null mice (7). Importantly, we have also shown local production of Prl (1, 8) and expression of Prl receptors in prostate epithelium (1, 9) and thereby provided evidence for an autocrine loop of Prl action in prostate. Downstream of Prl receptor activation, we have demonstrated that Stat5 is a key signaling protein in normal rat prostate epithelium (10) and that deficiency of Stat5 in Stat5a-null mice is associated with defective prostate tissue architecture (11).Stat5 is one of seven members of the Stat family of transcription factors in mammals (12) and consists of two distinct but highly homologous gene products: the 94-kDa Stat5a and 92-kDa Stat5b (13,14). In response to Prl, Stat5a and Stat5b become activated by phosphorylation on residue Tyr-694 and Tyr-699, respectively, in the C-terminal domain predominantly by Janus tyrosine kinase-2 (Jak2), which is preassociated with the cytoplasmic domain of the Prl receptor (15). Tyrosine-phosphorylated Stat5 proteins dimerize and translocate to the nucleus where they bind to specific response elements of target gene promoters to regulate transcription (16).Based on our previous findings of a survival function of Prl in normal prostate epitheli...

Suppressor of Cytokine Signaling-3 Antagonizes cAMP Effects on Proliferation and Apoptosis and Is Expressed in Human Prostate Cancer

“…Its activation in the prostate cancer correlates with high Gleason grade. 33,34 We and others demonstrated STAT3 phosphorylation in LNCaP cells in which growth was inhibited by IL-6 and found that 22Rv1 cells stimulated by IL-6 do not exhibit any phosphorylation of STAT3. 6,29,35 As noted by Clevenger, 13 the role of STAT3 is in breast cancer, similar to that in prostate cancer, incompletely understood.…”

Interleukin-7 induces apoptosis of 697 pre-B cells expressing dominant-negative forms of STAT5: evidence for caspase-dependent and -independent mechanisms

“…The expression of DN forms of STAT5A or STAT5B has previously been shown to affect the survival of various cell types (Mui et al, 1996;Dumon et al, 1999;Lord et al, 2000;Ahonen et al, 2003). In addition, deletion of stat5 genes in mouse can also disturb the survival and maturation of myeloid and erythroid progenitors cultured in the presence of granulocytemacrophage colony-stimulating-factor and erythropoietin (Socolovsky et al, 1999;Kieslinger et al, 2000).…”

Transcription factors: their potential as targets for an individualized therapeutic approach to cancer

“…BCR-ABL tyrosine kinase inhibitors can block STAT5 signaling 48 with consequent growth arrest and induction of apoptosis. Tommi et al 49 showed that STAT5 is activated in human prostate cancer cells. Inhibiting STAT5 leads to prostate cancer cell apoptosis.…”