Interleukin-6 regulates androgen synthesis in prostate cancer cells

Yeon Chun Jae, Nagalakshmi Nadiminty, Smitha Dutt, Wei Lou, Joy C. Yang, Hsing Jien Kung, Christopher P. Evans, Allen C. Gao

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Purpose: The standard systemic treatment for prostate cancer patients is androgen deprivation therapy. Although serum testosterone concentrations were significantly reduced after androgen deprivation therapy, levels of intraprostatic androgens are reproducibly measured at concentrations sufficient to activate androgen receptor and stimulate tumor growth, suggesting that prostate cancer cells may survive androgen deprivation therapies by increasing intracrine androgen synthesis within the prostate. However, factors that regulate de novo intracrine androgen synthesis have not been identified. Interleukin-6 (IL-6) has been implicated in the modulation of androgen receptor activation and growth and differentiation in prostate cancer. In this study, we investigate whether IL-6 regulates intraprostatic androgen synthesis in prostate cancer cells. Experimental Design: Quantitative reverse transcription-PCR and Western blotting were done to detect expression levels of steroidogenic enzymes. AKR1C3 promoter reporter was constructed and analyzed for IL-6-mediated AKR1C3 transcriptional activity. IL-6-mediated signaling was knocked down using small interfering RNA specific to IL-6 receptor and gp130, and the effect on AKR1C3 expression was examined. Intraprostatic androgen levels in prostate cancer cells in culture and in tumors were measured by an enzyme immunoassay (Testosterone EIA kit). Results: We found that IL-6 increases the expression of genes encoding many steroidogenic enzymes, including HSD3B2 and AKR1C3, involved in androgen biosynthesis. Down-regulation of IL-6 receptor and gp130 expression using specific small interfering RNA abolished IL-6-mediated AKR1C3 expression, suggesting that IL-6 signaling is responsible for AKR1C3 expression. IL-6 increases AKR1C3 promoter activity, indicating that the increase in IL-6-mediated AKR1C3 expression is in part at the transcriptional level. Treatment of IL-6 increased testosterone level in LNCaP cells. The tumor testosterone levels were detected at 378 pg/g in tumors generated from IL-6-overexpressing LNCaP-IL6+ cells inoculated orthotopically into the prostates of castrated male nude mice. Conclusions: These results suggest that IL-6 increases levels of intracrine androgens through enhanced expression of genes mediating androgen metabolism in prostate cancercells.

Original languageEnglish
Pages (from-to)4815-4822
Number of pages8
JournalClinical Cancer Research
Volume15
Issue number15
DOIs
Publication statusPublished - Aug 1 2009
Externally publishedYes

Fingerprint

Androgens
Interleukin-6
Prostatic Neoplasms
Testosterone
Interleukin-6 Receptors
Prostate
Androgen Receptors
Small Interfering RNA
Neoplasms
Therapeutics
Gene Expression
Enzymes
Growth
Immunoenzyme Techniques
Nude Mice
Reverse Transcription
Research Design
Down-Regulation
Cell Culture Techniques
Western Blotting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Jae, Y. C., Nadiminty, N., Dutt, S., Lou, W., Yang, J. C., Kung, H. J., ... Gao, A. C. (2009). Interleukin-6 regulates androgen synthesis in prostate cancer cells. Clinical Cancer Research, 15(15), 4815-4822. https://doi.org/10.1158/1078-0432.CCR-09-0640

Interleukin-6 regulates androgen synthesis in prostate cancer cells. / Jae, Yeon Chun; Nadiminty, Nagalakshmi; Dutt, Smitha; Lou, Wei; Yang, Joy C.; Kung, Hsing Jien; Evans, Christopher P.; Gao, Allen C.

In: Clinical Cancer Research, Vol. 15, No. 15, 01.08.2009, p. 4815-4822.

Research output: Contribution to journalArticle

Jae, YC, Nadiminty, N, Dutt, S, Lou, W, Yang, JC, Kung, HJ, Evans, CP & Gao, AC 2009, 'Interleukin-6 regulates androgen synthesis in prostate cancer cells', Clinical Cancer Research, vol. 15, no. 15, pp. 4815-4822. https://doi.org/10.1158/1078-0432.CCR-09-0640
Jae, Yeon Chun ; Nadiminty, Nagalakshmi ; Dutt, Smitha ; Lou, Wei ; Yang, Joy C. ; Kung, Hsing Jien ; Evans, Christopher P. ; Gao, Allen C. / Interleukin-6 regulates androgen synthesis in prostate cancer cells. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 15. pp. 4815-4822.
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AU - Yang, Joy C.

AU - Kung, Hsing Jien

AU - Evans, Christopher P.

AU - Gao, Allen C.

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N2 - Purpose: The standard systemic treatment for prostate cancer patients is androgen deprivation therapy. Although serum testosterone concentrations were significantly reduced after androgen deprivation therapy, levels of intraprostatic androgens are reproducibly measured at concentrations sufficient to activate androgen receptor and stimulate tumor growth, suggesting that prostate cancer cells may survive androgen deprivation therapies by increasing intracrine androgen synthesis within the prostate. However, factors that regulate de novo intracrine androgen synthesis have not been identified. Interleukin-6 (IL-6) has been implicated in the modulation of androgen receptor activation and growth and differentiation in prostate cancer. In this study, we investigate whether IL-6 regulates intraprostatic androgen synthesis in prostate cancer cells. Experimental Design: Quantitative reverse transcription-PCR and Western blotting were done to detect expression levels of steroidogenic enzymes. AKR1C3 promoter reporter was constructed and analyzed for IL-6-mediated AKR1C3 transcriptional activity. IL-6-mediated signaling was knocked down using small interfering RNA specific to IL-6 receptor and gp130, and the effect on AKR1C3 expression was examined. Intraprostatic androgen levels in prostate cancer cells in culture and in tumors were measured by an enzyme immunoassay (Testosterone EIA kit). Results: We found that IL-6 increases the expression of genes encoding many steroidogenic enzymes, including HSD3B2 and AKR1C3, involved in androgen biosynthesis. Down-regulation of IL-6 receptor and gp130 expression using specific small interfering RNA abolished IL-6-mediated AKR1C3 expression, suggesting that IL-6 signaling is responsible for AKR1C3 expression. IL-6 increases AKR1C3 promoter activity, indicating that the increase in IL-6-mediated AKR1C3 expression is in part at the transcriptional level. Treatment of IL-6 increased testosterone level in LNCaP cells. The tumor testosterone levels were detected at 378 pg/g in tumors generated from IL-6-overexpressing LNCaP-IL6+ cells inoculated orthotopically into the prostates of castrated male nude mice. Conclusions: These results suggest that IL-6 increases levels of intracrine androgens through enhanced expression of genes mediating androgen metabolism in prostate cancercells.

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