Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer

Abstract

Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen-liganded (MDV3100, Bicalutamide, Flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the Prostate Specific Antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using antiandrogens may be substantially improved by targeting of Stat5a/b.

Cell-Free DNA Modification Dynamics in Abiraterone Acetate-Treated Prostate Cancer Patients

“…For instance, STAT5A, which is known to be upregulated in prostate cancer (28), showed reduced modification during treatment in two cytosines covering 5 0 UTR region. STAT5A/B directly interact with androgen receptors and increase their activity, as well as protect antiandrogen-bound androgen receptors from degradation in proteasomes (29,30). Consistently, STAT5A/B enable prostate cancer cells that do not express androgen receptors to survive by switching to an androgenindependent growth (28,31).…”

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

“…Jak2-Stat5 signaling inhibitors potently suppress the growth and induce apoptosis of primary prostate cancer cells and castrate-resistant prostate cancer cells, this inhibitory effect was observed in 75% of primary tumors grown ex vivo in organ explant cultures [439]. Therapeutic targeting of AR in prostate cancer using antiandrogens may be considerably enhanced by targeting of Stat5, through a stimulation of proteosomal degradation of AR liganded by antiandrogens [440]. Studies in experimental models support the concept that Stat5 signaling promotes metastatic progression of prostate cancer by inducing epithelial to mesenchymal transition and stem cell properties in prostate cancer cells [441].…”

Drosophila Jak/STAT Signaling: Regulation and Relevance in Human Cancer and Metastasis

“…As with other carcinomas, Jak/STAT core components, IL-6, Jak2, and STAT5, and other key regulators of this pathway are implicated in promotion of prostate tumor growth and metastasis, and there is no highly effective treatment to cure metastatic disease. Activated STAT5a/b indicates a poor prognosis [163]. Abnormal STAT5 activation was detected in over 60% of distant prostate cancer metastasis, including over 80% of those in lymph nodes in human clinical samples [164].…”

“…However, this mechanism might be dependent on Src kinases instead of Jak. STAT5 has been shown to interact with the androgen receptor, via its DNA binding domain, and protect it against proteosomal degradation, which can induce tumor growth in prostate cancer cells and may not require Jak [163]. The IL-6 receptor has also been shown to promote prostate cancer metastasis.…”