Aberrant Activation Of Androgen Receptor In A New Neuropeptide-Autocrine Model Of Androgen-Insensitive Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 01 Mar 2009 - 1:00 PDT

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UroToday.com - In the January 2009 issue of Cancer Research, Dr. Joy Yang and colleagues reported a new animal model of neuropeptide mediated prostate cancer (CaP). Neuropeptides are released by CaP cells at the time of androgen deprivation. They are one of 5 mechanisms that can facilitate castration-resistant CaP growth.

In these studies, the neuropeptide gastrin-releasing peptide was overexpressed in androgen-sensitive LNCaP cells. Compared to mock transfected cells, the LNCaP-GRP cells demonstrated androgen-independent growth and migration and tumorigenic growth on androgen-depleted soft agar.

These events were inhibited by both the anti-androgen bicalutamide and a monoclonal antibody against GRP. Orthotopic injection of LNCaP-GRP cells in castrated nude mice resulted in large primary tumor growth, with expression of GRP, PSA and nuclear translocation of AR supporting the castration-resistant properties.

The xenograft tumors were extracted and regrown in vitro. The recultured tumor lines were able to transactivate a PSA-luciferase construct without the addition of synthetic androgen. Chromatin immunoprecipitation experiments were performed to analyze which androgen response elements (ARE) in a PSA gene construct were bound with activated AR in LNCaP-GRP cells. AR bound primarily to the proximal promoter ARE region in LNCaP-GRP cells even in the absence of androgen. In comparison, LNCaP mock cells stimulated with androgen directed AR preferentially to the ARE in the enhancer region. This suggests that AR is differentially bound to AREs when activated by different ligands.

Experiments demonstrated that the GRP activation of AR was mediated through a complex of the non-receptor tyrosine kinases Src, FAK and Etk. LNCaP-GRP cell treatment with the Src-specific inhibitor AZD0530 abrogated the activation of AR and its nuclear translocation. This was confirmed by merging immunofluorescent staining of AR and DAPI with a 50% reduction in AR nuclear translocation.

The LNCaP-GRP tumors were orthotopically injected in castrated SCID mice. All control mice grew primary tumors with lymph node metastasis. Beginning 2 weeks after tumor injection, the treated mice were fed the oral Src inhibitor AZD0530. Five of 7 treated animals grew primary tumors, but none had lymph node metastasis. The serum PSA levels in treated animals were significantly lower than control mice.

These data support the hypothesis that neuropeptide expression by CaP tumors confer castration resistant growth and metastasis. This occurs via Src kinase mediated activation of the androgen receptor. Use of an oral, Src-specific inhibitor resulted in inhibition of this process in vitro and in mice. AZD0530 is presently in Phase II trials for patients with metastatic CaP.

Yang JC, Ok JH, Busby JE, Borowsky AD, Kung HJ, Evans CP
Cancer Res. 2009 Jan 1;69(1):151-60.
doi:10.1158/0008-5472.CAN-08-0442

Written by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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