title: Androgen receptor activation in castration-recurrent prostate cancer: the role of Src-family and Ack1 tyrosine kinases.
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.
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Irwin H
authors.initials: IH
authors.lastname: Gelman
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C410798:AR protein, human; D000728:Androgens; D011944:Receptors, Androgen; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human
keywords: Ack1; Src-family tyrosine kinases; androgen receptor; castration-recurrence.; prostate cancer