Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer

Abstract

The main cause of prostate cancer-related mortality is the development of hormone-refractory disease. Circulating serum levels of IL-6 are raised in hormone-refractory prostate cancer patients and evidence from cell line studies suggests that the IL-6R/JAK/STAT3 pathway may be involved in development of this disease. In the current study we investigate if expression levels of these family members are implicated in the development of hormone-refractory prostate cancer. Immunohistochemistry using IL-6R, JAK1, STAT3, pSTAT3 Tyr705 and pSTAT3 Ser727 antibodies was performed on 50 matched hormone-sensitive and hormone-refractory tumours pairs. An increase in expression of cytoplasmic IL-6 receptor, with the development of hormone-refractory prostate cancer was associated with reduced time to relapse (P ¼ 0.0074) while an increase in expression of cytoplasmic pSTAT3 Tyr705 was associated with reduced patient survival (P ¼ 0.0003). In addition, those patients with high expression of cytoplasmic pSTAT3 Tyr705 in their hormone-refractory tumours had significantly shorter time to death from biochemical relapse and overall survival in comparison to those patients with low expression of cytoplasmic pSTAT3 Tyr705 (P ¼ 0.002 and P ¼ 0.0027, respectively). Activation of STAT3, via phosphorylation is associated with reduced patient survival, suggesting that activation of the IL-6R/JAK/STAT3 pathway is involved with development of hormone-refractory prostate cancer.

Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells

“…These results are consistent with recent studies demonstrating that low or negative levels of AR and PSA are associated with tumor-propagating cells in prostate cancer xenografts (18,19,33,34). Low levels of AR and PSA are also characteristic of DU145 (35) (38). Myc and myrAKT-driven tumor cells exhibited low levels of phosphorylated Erk1/2, downstream of the MAPK pathway, and weak staining for phosphorylated STAT3, a readout of the JAK/STAT pathway (Fig.…”

Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells

“…24,25 Obesity-induced prostate 26,27 cancer progression may be attributed to dysregulated levels of growth factors and cytokines. [28][29][30] However, the mechanism(s) by which obesity promotes invasive prostate cancer remains unclear. Independently, abnormal levels of IGF-1, leptin and IL-6, proteins, often upregulated due to obesity, have been shown to contribute to invasive prostate cancer.…”

STAT3 as a target for inducing apoptosis in solid and hematological tumors

“…In that regard, the presence of activated STAT3 has been detected in prostate cancer tissue samples [70]. Investigative studies have shown that aberrant STAT3 activation in prostate cancer cells is associated with signal transduction from the IL-6 and IL-11 cytokines, and is mediated by kinase activities of the EGFR and Jak families [38,71]. The mechanisms for STAT3-mediated prostate cancer development are currently under investigation.…”