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Updated: Feb 18, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
STAT3 and STAT5A are potential therapeutic targets in castration-resistant prostate cancer
Sambit K Mohanty1, Kader Yagiz2, Dinesh Pradhan3
1Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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.
Insights
STAT3 and STAT5A are highly expressed in castration-resistant prostate cancer (CRPC), suggesting their role in disease progression. Targeting STAT3/5A may offer a new therapeutic strategy for advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Mechanisms of castration-resistant prostate cancer (CRPC) are poorly understood, limiting effective drug development.
- Activation of Signal Transducer and Activator of Transcription 3/5A (STAT3/5A) is linked to aggressive prostate cancer (PC), but their specific role in CRPC is unclear.
Purpose of the Study:
- To investigate the role of STAT3/5A in CRPC.
- To evaluate STAT3/5A as potential biomarkers for therapeutic efficacy in advanced PC.
Main Methods:
- Immunohistochemistry to assess STAT3/5A protein expression in CRPC and benign prostatic hyperplasia (BPH) tissues.
- Quantitative mRNA expression profiling of STAT3/5A in PC cells.
- Pharmacological inhibition of STAT5 using pimozide.
- Analysis of public PC datasets for gene amplification.
Main Results:
- High nuclear expression of STAT3 (93%) and STAT5A (80%) was observed in CRPC compared to BPH.
- PC cells express varying levels of STAT3 and STAT5A transcripts.
- Pimozide inhibited PC cell growth and induced apoptosis in a dose-dependent manner.
- STAT3/5A genes were frequently amplified in metastatic CRPC.
Conclusions:
- STAT3/5A are potential predictive biomarkers for evaluating JAK/STAT pathway-targeted cancer drugs.
- Inhibition of JAK/STAT signaling, potentially combined with androgen receptor (AR) pathway inhibition, could represent a novel treatment strategy for advanced PC.
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