Uncarboxylated Osteocalcin and Gprc6a Axis Produce Intratumoral Androgens in Castration-Resistant Prostate Cancer
Annual rept. 1 Mar 2014-28 Feb 2015
WAYNE STATE UNIV DETROIT MI
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Castrate resistant prostate cancer CRPC represents the final and lethal disease state in the progression of prostate cancer. CRPC patients often develop bone metastasis resulting in bone fractures and morbidity. Recently, tumor cells have been shown to activate androgen receptor signaling via multiple pathways, despite castrate levels of testosterone. One such adaptive mechanism is the intracrine production of androgens in the primary tumor andor at metastatic sites by the activity of androgen biosynthetic enzymes. Recent study shows that Gprc6aOsteocalcin axis regulates physiological androgen biosynthesis in testis. Since Osteocalcin is overexpressed in patients with bone metastasis and existence of intratumoral androgen synthesis in bone metastasis, we hypothesized that bone tumor expressed Osteocalcin can induce intratumoral androgen synthesis in bone metastasis. We show that in VCaP model system Gprc6a is expressed and overexpression of its ligand Osteocalcin in these cells leads to expression of androgen biosynthetic enzymes. This data suggest that prostate cancer bone tumors hijack OsteocalcinGprc6a axis for the production of intratumoral androgens via overexpression of certain androgen biosynthetic enzyme expression. Bone tumor expressed androgens promote disease progression via tumoral androgen production and androgen receptor activation.
- Medicine and Medical Research