STAT3 and STAT5a Are Potential Therapeutic Targets in Castration-Resistant Prostate Cancer
Sambit K Mohanty, Kader Yagiz, Bekir Cinar, Mahul B Amin, Daniel Luthringer, Serhan Alkan. Cedars-Sinai Medical Center, Los Angeles, CA
Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant prostate cancer (mCRPCa). The neoplastic cells develop resistance to androgen deprivation therapy within two to three years of therapy. The molecular mechanisms underlying this progression are not clearly defined, thus hindering rational-based drug design. Signal transducer and activator of transcription 3 (STAT3) and 5a/b (STAT5a/b) are suggested to play a role in promoting growth of high-grade hormone-resistant (HGR) PCa. Although molecular studies have shown expression of STAT3 and STAT5 on PCa cell lines, expression of STAT3 and STAT5 on tissue sections of HGRPCa are not studied. This study aims to determine possible role of STAT3 and STAT5a in HGRPCa.
Design: The anatomic pathology database was searched for HGRPCa after Institutional Review Board approval. We examined nuclear expression of STAT3 and STAT5a by immunohistochemistry (IHC) and the results were compared to fifteen cases of benign prostatic hypertrophy (BPH). In addition, we tested effects of STAT inhibitor (Pimozide) at 72 hours in androgen sensitive LNCaP and castration resistant LNCaP subline (C4-2) PCa cell models by assessing proliferative response to various concentrations (0, 5, 10 and 20 micromolar) in serum fed growth condition.
Results: Fifteen cases of HGRPCa and 15 cases of BPH were used for IHC assessment. Age ranged from 59 to 95 years (median = 81) in the former and 57 to 86 years (median = 68) in the latter category. The details of results of STAT3 and STAT5a immunostaining are illustrated in Table 1. Treatment with Pimozide showed a significant inhibition of LNCaP cell proliferation at 10 micromolar and of C4-2 cell proliferation at 20 micromolar concentration.
Conclusions: Our results demonstrate expression of STAT3 and STAT5a on tissue sections may potentially serve as a predictive marker of responsiveness to therapies targeting JAK/STAT pathway. Since JAK/STAT and androgen receptor (AR) signaling pathways functionally synergize in the neoplastic cells and may be involved in the progression of PCa, the inhibition of JAK/STAT alone or in combination with AR signaling may lead to a novel treatment modality for patients with CRPCa.
Monday, March 4, 2013 1:00 PM
Poster Session II # 279, Monday Afternoon