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Int J Biol Sci 2014; 10(6):620-626. doi:10.7150/ijbs.8264

Review

Androgen Receptor Activation in Castration-Recurrent Prostate Cancer: The Role of Src-Family and Ack1 Tyrosine Kinases

Irwin H. Gelman

Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Abstract

There is growing appreciation that castration-recurrent prostate cancer (CR-CaP) is driven by the continued expression of androgen receptor (AR). AR activation in CR-CaP through various mechanisms, including AR overexpression, expression of AR splice variants or mutants, increased expression of co-regulator proteins, and by post-translational modification, allows for the induction of AR-regulated genes in response to very low levels of tissue-expressed, so-called intracrine androgens, resulting in pathways that mediate CaP proliferation, anti-apoptosis and oncogenic aggressiveness. The current review focuses on the role played by Src-family (SFK) and Ack1 non-receptor tyrosine kinases in activating AR through direct phosphorylation, respectively, on tyrosines 534 or 267, and how these modifications facilitate progression to CR-CaP. The fact that SFK and Ack1 are central mediators for multiple growth factor receptor signaling pathways that become activated in CR-CaP, especially in the context of metastatic growth in the bone, has contributed to recent therapeutic trials using SFK/Ack1 inhibitors in monotherapy or in combination with antagonists of the AR activation axis.

Keywords: Src-family tyrosine kinases, Ack1, androgen receptor, prostate cancer, castration-recurrence.

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How to cite this article:
Gelman IH. Androgen Receptor Activation in Castration-Recurrent Prostate Cancer: The Role of Src-Family and Ack1 Tyrosine Kinases. Int J Biol Sci 2014; 10(6):620-626. doi:10.7150/ijbs.8264. Available from http://www.ijbs.com/v10p0620.htm