STAT3 and STAT5A are potential therapeutic targets in castration-resistant prostate cancer
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Sambit K. Mohanty1, Kader Yagiz2, Dinesh Pradhan3, Daniel J. Luthringer1, Mahul B. Amin4, Serhan Alkan1 and Bekir Cinar5,6
1Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
2Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
3University of Pittsburgh Medical Center, Pittsburgh, PA 15238, USA
4Department of Pathology and Laboratory Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA
5Department of Biological Sciences, The Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
6Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
Serhan Alkan, email: [email protected]
Bekir Cinar, email: [email protected]
Keywords: STAT3, STAT5A, pimozide, castration-resistance, prostate cancer
Received: April 26, 2017 Accepted: August 03, 2017 Published: September 12, 2017
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.
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