Androgen receptor regulation of local growth hormone in prostate cancer cells

M. Victoria Recouvreux, J. Boyang Wu, Allen C Gao, Svetlana Zonis, Vera Chesnokova, Neil Bhowmick, Leland W. Chung, Shlomo Melmed

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Abstract

Prostate cancer (PCA) growth is mainly driven by androgen receptor (AR), and tumors that initially respond to androgen deprivation therapy (ADT) or AR inhibition usually relapse into a more aggressive, castration-resistant PCA (CRPC) stage. Circulating growth hormone (GH) has a permissive role in PCA development in animal models and in human PCA xenograft growth. As GH and GH receptor (GHR) are both expressed in PCA cells, we assessed whether prostatic GH production is linked to AR activity and whether GH contributes to the castration-resistant phenotype. Using online datasets, we found that GH is highly expressed in human CRPC. We observed increased GH expression in castration-resistant C4-2 compared with castration-sensitive LNCaP cells as well as in enzalutamide (MDV3100)-resistant (MDVR) C4-2B (C4-2B MDVR) cells compared with parental C4-2B.Wedescribe a negative regulation of locally producedGHby androgens/AR in PCA cells following treatment with AR agonists (R1881) and antagonists (enzalutamide, bicalutamide). We also show that GH enhances invasive behavior of CRPC 22Rv1 cells, as reflected by increased migration, invasion, and anchorage-independent growth, as well as expression of matrix metalloproteases. Moreover, GH induces expression of the AR splice variant 7, which correlates with antiandrogen resistance, and also induces insulinlike growth factor 1,which is implicated in PCA progression and ligandindependent AR activation. In contrast, blockade of GH action with the GHR antagonist pegvisomant reverses these effects both in vitro and in vivo. GH induction following ADT or AR inhibition may contribute to CRPC progression by bypassing androgen growth requirements.

Original languageEnglish (US)
Pages (from-to)2255-2268
Number of pages14
JournalEndocrinology
Volume158
Issue number7
DOIs
StatePublished - Jul 1 2017

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ASJC Scopus subject areas

  • Endocrinology

Cite this

Recouvreux, M. V., Wu, J. B., Gao, A. C., Zonis, S., Chesnokova, V., Bhowmick, N., Chung, L. W., & Melmed, S. (2017). Androgen receptor regulation of local growth hormone in prostate cancer cells. Endocrinology, 158(7), 2255-2268. https://doi.org/10.1210/en.2016-1939