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The Neuroendocrine-Derived Peptide Parathyroid Hormone–Related Protein Promotes Prostate Cancer Cell Growth by Stabilizing the Androgen Receptor

Department of Microbiology and Cancer Center, University of Virginia Health System, Charlottesville, Virginia

Requests for reprints: Sarah J. Parsons, Department of Microbiology, University of Virginia Health System, P. O. Box 800734, Charlottesville, VA 22908-0734. Phone: 434-924-2352; Fax: 434-982-0689; E-mail: sap{at}virginia.edu.

Key Words: androgen receptor • neuroendocrine differentiation • PTHrP • EGFR • Src

During progression to an androgen-independent state following androgen ablation therapy, prostate cancer cells continue to express the androgen receptor (AR) and androgen-regulated genes, indicating that AR is critical for the proliferation of hormone-refractory prostate cancer cells. Multiple mechanisms have been proposed for the development of AR-dependent hormone-refractory disease, including changes in expression of AR coregulatory proteins, AR mutation, growth factor–mediated activation of AR, and AR protein up-regulation. The most prominent of these progressive changes is the up-regulation of AR that occurs in >90% of prostate cancers. A common feature of the most aggressive hormone-refractory prostate cancers is the accumulation of cells with neuroendocrine characteristics that produce paracrine factors and may provide a novel mechanism for the regulation of AR during advanced stages of the disease. In this study, we show that neuroendocrine-derived parathyroid hormone–related protein (PTHrP)–mediated signaling through the epidermal growth factor receptor (EGFR) and Src pathways contributes to the phenotype of advanced prostate cancer by reducing AR protein turnover. PTHrP-induced accumulation of AR depended on the activity of Src and EGFR and consequent phosphorylation of the AR on Tyr⁵³⁴. PTHrP-induced tyrosine phosphorylation of AR resulted in reduced AR ubiquitination and interaction with the ubiquitin ligase COOH terminus of Hsp70-interacting protein. These events result in increased accumulation of AR and thus enhanced growth of prostate cancer cells at low levels of androgen. [Cancer Res 2009;69(18):7402–11]