Am J Clin Exp Urol 2013;1(1):53-65
Original Article
Anti-androgen resistance in prostate cancer cells chronically induced
by interleukin-1β
Julia A Staverosky, Xin-Hua Zhu, Susan Ha, Susan K Logan
Departments of Biochemistry and Molecular Pharmacology, Medicine, Division of Hematology and Oncology,
Urology, New York University Cancer Institute, New York University School of Medicine, New York, NY, USA;
Departments of Chemistry, Global Health, University of Washington, Seattle, WA USA. Equal contributors.
Received November 25, 2013; Accepted December 18, 2013; Epub December 25, 2013; Published December 30,
2013
Abstract: Chronic inflammation has been linked to cancer initiation and progression in a variety of tissues, yet the
impact of acute and chronic inflammatory signaling on androgen receptor function has not been widely studied. In
this report, we examine the impact of the inflammation-linked cytokine, interleukin-1β on androgen receptor
function in prostate cancer cells. We demonstrate that acute interleukin-1β treatment inhibits the transcription of
the androgen receptor gene itself, resulting in the reduction of androgen receptor protein levels. Interestingly, in
cells subjected to chronic interleukin-1β stimulation, the transcription of the androgen receptor gene is restored
within a few cell passages and the cells acquire the ability to grow in the presence of the anti-androgen,
bicalutamide. Importantly, the changes that accompany this loss of androgen receptor regulation and gain of anti-
androgen resistance are stably heritable since once established, the phenotype is maintained even in the
absence of exogenously added interleukin-1β. Further, bicalutamide resistance correlates with increased
transcription of androgen receptor target genes and histone H3K4 dimethylation at M-phase gene enhancers.
Overall, our studies demonstrate a novel route to anti-androgen resistance upon exposure to an inflammatory
cytokine and provide a new tool to further understand how anti-androgen resistance emerges under chronic
inflammation. (AJCEU1311002).
Keywords: Interleukin-1β, inflammation, bicalutamide resistance, castration resistant prostate cancer, androgen
receptor
Address correspondence to: Dr. Susan K Logan, Departments of Urology and Biochemistry and Molecular
Pharmacology, New York University Cancer Institute, New York University School of Medicine, 550 First Ave,
MSB424, New York, NY 10016. Tel: 212-263-2921; Fax: 212-263-7133; E-mail: susan.logan@nyumc.org
Original Article
Anti-androgen resistance in prostate cancer cells chronically induced
by interleukin-1β
Julia A Staverosky, Xin-Hua Zhu, Susan Ha, Susan K Logan
Departments of Biochemistry and Molecular Pharmacology, Medicine, Division of Hematology and Oncology,
Urology, New York University Cancer Institute, New York University School of Medicine, New York, NY, USA;
Departments of Chemistry, Global Health, University of Washington, Seattle, WA USA. Equal contributors.
Received November 25, 2013; Accepted December 18, 2013; Epub December 25, 2013; Published December 30,
2013
Abstract: Chronic inflammation has been linked to cancer initiation and progression in a variety of tissues, yet the
impact of acute and chronic inflammatory signaling on androgen receptor function has not been widely studied. In
this report, we examine the impact of the inflammation-linked cytokine, interleukin-1β on androgen receptor
function in prostate cancer cells. We demonstrate that acute interleukin-1β treatment inhibits the transcription of
the androgen receptor gene itself, resulting in the reduction of androgen receptor protein levels. Interestingly, in
cells subjected to chronic interleukin-1β stimulation, the transcription of the androgen receptor gene is restored
within a few cell passages and the cells acquire the ability to grow in the presence of the anti-androgen,
bicalutamide. Importantly, the changes that accompany this loss of androgen receptor regulation and gain of anti-
androgen resistance are stably heritable since once established, the phenotype is maintained even in the
absence of exogenously added interleukin-1β. Further, bicalutamide resistance correlates with increased
transcription of androgen receptor target genes and histone H3K4 dimethylation at M-phase gene enhancers.
Overall, our studies demonstrate a novel route to anti-androgen resistance upon exposure to an inflammatory
cytokine and provide a new tool to further understand how anti-androgen resistance emerges under chronic
inflammation. (AJCEU1311002).
Keywords: Interleukin-1β, inflammation, bicalutamide resistance, castration resistant prostate cancer, androgen
receptor
Address correspondence to: Dr. Susan K Logan, Departments of Urology and Biochemistry and Molecular
Pharmacology, New York University Cancer Institute, New York University School of Medicine, 550 First Ave,
MSB424, New York, NY 10016. Tel: 212-263-2921; Fax: 212-263-7133; E-mail: susan.logan@nyumc.org
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