STAT3 and STAT5A are potential therapeutic targets in castration-resistant prostate cancer

// Sambit K. Mohanty 1 , Kader Yagiz 2 , Dinesh Pradhan 3 , Daniel J. Luthringer 1 , Mahul B. Amin 4 , Serhan Alkan 1 and Bekir Cinar 5, 6 1 Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 2 Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 3 University of Pittsburgh Medical Center, Pittsburgh, PA 15238, USA 4 Department of Pathology and Laboratory Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA 5 Department of Biological Sciences, The Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA 6 Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA Correspondence to: Serhan Alkan, email: serhan.alkan@cshs.org Bekir Cinar, email: bcinar@cau.edu Keywords: STAT3, STAT5A, pimozide, castration-resistance, prostate cancer Received: April 26, 2017     Accepted: August 03, 2017     Published: September 12, 2017 ABSTRACT Mechanisms of castration-resistant prostate cancer (CRPC) are not well understood, thus hindering rational-based drug design. Activation of STAT3/5A, key components of the JAK/STAT pathway, is implicated in aggressive PC, yet their clinical relevance in CRPC remains elusive. Here, we evaluated the possible role of STAT3/5A in CRPC using immunological, quantitative mRNA expression profiling, and pharmacological methods. We observed a strong nuclear immunoreactivity for STAT3 and STAT5A in 93% (n=14/15) and 80% (n=12/15) of CRPC cases, respectively, compared with benign prostatic hyperplasia (BPH). We demonstrated that PC cells express varying levels of STAT3 and STAT5A transcripts. In addition, we demonstrate that pimozide, a psychotropic drug and an indirect inhibitor of STAT5, attenuated PC cells growth, and induced apoptosis in a dose-dependent manner. Furthermore, our analysis of the PC public data revealed that the STAT3/5A genes were frequently amplified in metastatic CRPC. These findings suggest that STAT3/5A potentially serves as a predictive biomarker to evaluate the therapeutic efficacy of a cancer drug targeting the JAK/STAT pathway. Since the JAK/STAT and AR pathways are suggested to be functionally synergistic, inhibition of the JAK/STAT signaling alone or together with AR may lead to a novel treatment modality for patients with advanced PC.