The neuroendocrine-derived peptide parathyroid hormone-related protein promotes prostate cancer cell growth by stabilizing the androgen receptor.
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 Tyr(534). 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.
DaSilva
John
J
Department of Microbiology and Cancer Center, University of Virginia Health System, Charlottesville, Virginia 22908-0734, USA.
Gioeli
Daniel
D
Weber
Michael J
MJ
Parsons
Sarah J
SJ
D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D018841:HSP90 Heat-Shock Proteins; D044162:Parathyroid Hormone-Related Protein; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D015741:Metribolone; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D019061:src-Family Kinases
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