Aberrant Activation of Androgen Receptor in a New Neuropeptide-Autocrine Model of Androgen-Insensitive Prostate Cancer

Abstract

Treatment of advanced prostate cancer with androgen deprivation therapy inevitably renders the tumors castration-resistant and incurable. Under these conditions, neuroendocrine differentiation of prostate cancer (CaP) cells is often detected and neuropeptides released by these cells may facilitate the development of androgen independence. Exemplified by gastrin-releasing peptide (GRP), these neuropeptides transmit their signals through G protein-coupled receptors, which are often overexpressed in prostate cancer, and aberrantly activate androgen receptor (AR) in the absence of androgen. We developed an autocrine neuropeptide model by overexpressing GRP in LNCaP cells and the resultant cell line, LNCaP-GRP, exhibited androgen-independent growth with enhanced motility in vitro . When orthotopically implanted in castrated nude mice, LNCaP-GRP produced aggressive tumors, which express GRP, prostate-specific antigen, and nuclear-localized AR. Chromatin immunoprecipitation studies of LNCaP-GRP clones suggest that GRP activates and recruits AR to the cognate promoter in the absence of androgen. A Src family kinase (SFK) inhibitor, AZD0530, inhibits androgen-independent growth and migration of the GRP-expressing cell lines, and blocks the nuclear translocation of AR, indicating the involvement of SFK in the aberrant activation of AR and demonstrating the potential use of SFK inhibitor in the treatment of castration-resistant CaP. In vivo studies have shown that AZD0530 profoundly inhibits tumor metastasis in severe combined immunodeficient mice implanted with GRP-autocrine LNCaP cells. This xenograft model shows autocrine, neuropeptide-and Src kinasemediated progression of androgen-independent CaP postcastration, and is potentially useful for testing novel therapeutic agents. [Cancer Res 2009;69(1):151-60]

GRPR antagonists for prostate cancer—prospects and caveats

“…4 These findings strongly indicate that the GRPR can mediate cancer initiation and growth by modulating AR signalling, even in the absence of androgen stimulation. Thus, the GRPR is a particularly promising target for the inhibition of tumour progression in patients with castration-resistant prostate cancer.…”

Effect of the Specific Src Family Kinase Inhibitor Saracatinib on Osteolytic Lesions Using the PC-3 Bone Model

“…New therapeutic strategies such as small-molecule inhibitors of signaling pathways responsible for cancer progression are desirable. Src kinase has been implicated in prostate tumor proliferation, migration, survival (23,35,36), and progression to castration resistance (26). Many recently developed small-molecule SFK inhibitors, including bosutinib (SKI-606; ref.…”

“…38,39), and saracatinib are able to reduce the proliferation, migration, and invasion of prostate cancer cell lines in vitro and are currently in clinical trials. These inhibitors also decrease prostate cancer growth and metastasis in mouse xenograft studies (26,29,39). Recent studies using saracatinib showed that Src has a pivotal role in the formation and activation of human osteoclasts (40) and is involved in breast cancer bone metastasis regardless of the estrogen receptor status (41).…”

“…Our previous studies showed that Src kinase plays an important role in promoting androgen-independent prostate tumor growth (23)(24)(25)(26). Upregulation of Src family kinase (SFK) activities has been reported in 28% of androgen-independent prostate cancer patients (27).…”

“…As a result, tumor metastasis was profoundly inhibited in an animal study using castration-resistant LNCaP expressing neuropeptide gastrin-releasing peptide (LNCaP-GRP cells; ref. 26).…”