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Updated: Jun 10, 2026
miRNA Expression Analyses in Prostate Cancer Clinical Tissues
Published on: September 8, 2015
Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer
Philippe O Gannon1, Jessica Godin-Ethier, Matthew Hassler
1Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de Montréal, Montreal, Quebec, Canada.
Background:
Prostate cancer (PCa) is the most frequently diagnosed cancer in North American men. Androgen-deprivation therapy (ADT) accentuates the infiltration of immune cells within the prostate. However, the immunosuppressive pathways regulated by androgens in PCa are not well characterized. Arginase 2 (ARG2) expression by PCa cells leads to a reduced activation of tumor-specific T cells. Our hypothesis was that androgens could regulate the expression of ARG2 by PCa cells.
Methodology/Principal Findings:
In this report, we demonstrate that both ARG1 and ARG2 are expressed by hormone-sensitive (HS) and hormone-refractory (HR) PCa cell lines, with the LNCaP cells having the highest arginase activity. In prostate tissue samples, ARG2 was more expressed in normal and non-malignant prostatic tissues compared to tumor tissues. Following androgen stimulation of LNCaP cells with 10 nM R1881, both ARG1 and ARG2 were overexpressed. The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. Patients treated by ADT prior to surgery had lower ARG2 expression in both non-malignant and malignant tissues. Furthermore, ARG1 and ARG2 were enzymatically active and their decreased expression by siRNA resulted in reduced overall arginase activity and l-arginine metabolism. The decreased ARG1 and ARG2 expression also translated with diminished LNCaP cells cell growth and increased PBMC activation following exposure to LNCaP cells conditioned media. Finally, we found that interleukin-8 (IL-8) was also upregulated following androgen stimulation and that it directly increased the expression of ARG1 and ARG2 in the absence of androgens.
Conclusion/Significance:
Our data provides the first detailed in vitro and in vivo account of an androgen-regulated immunosuppressive pathway in human PCa through the expression of ARG1, ARG2 and IL-8.
Insights
Androgens regulate immunosuppression in prostate cancer (PCa) by increasing arginase 1 (ARG1) and arginase 2 (ARG2) expression, which hinders T cell activation. This androgen-driven pathway involves interleukin-8 (IL-8) and impacts PCa cell growth.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Prostate cancer (PCa) is a prevalent cancer in North American men.
- Androgen-deprivation therapy (ADT) increases immune cell infiltration in the prostate.
- Androgen-regulated immunosuppressive pathways in PCa are not fully understood.
- Arginase 2 (ARG2) expression by PCa cells reduces tumor-specific T cell activation.
Purpose of the Study:
- To investigate the hypothesis that androgens regulate the expression of arginase 2 (ARG2) by PCa cells.
- To elucidate the role of androgens in PCa-associated immunosuppression.
Main Methods:
- Assessed arginase 1 (ARG1) and ARG2 expression in PCa cell lines (LNCaP) and prostate tissues.
- Stimulated LNCaP cells with R1881 (androgen) and used siRNA targeting the androgen receptor (AR).
- Performed immunohistochemistry on patient samples from patients treated with ADT.
- Measured arginase activity, L-arginine metabolism, cell growth, and peripheral blood mononuclear cell (PBMC) activation.
- Investigated the role of interleukin-8 (IL-8) in androgen-stimulated arginase expression.
Main Results:
- Both ARG1 and ARG2 are expressed in hormone-sensitive and hormone-refractory PCa cell lines.
- Androgen stimulation of LNCaP cells led to ARG1 and ARG2 overexpression, dependent on the androgen receptor (AR).
- ADT-treated patients showed lower ARG2 expression in prostate tissues.
- Decreased ARG1 and ARG2 expression reduced arginase activity, L-arginine metabolism, and PCa cell growth, while increasing PBMC activation.
- Interleukin-8 (IL-8) was upregulated by androgens and directly increased ARG1 and ARG2 expression.
Conclusions:
- This study provides the first detailed in vitro and in vivo evidence of an androgen-regulated immunosuppressive pathway in human PCa.
- The pathway involves the expression of ARG1, ARG2, and IL-8.
- Understanding this pathway offers potential therapeutic targets for PCa treatment.
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