Inhibition of human chorionic gonadotropin β‐subunit modulates the mitogenic effect of c‐myc in human prostate cancer cells

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Abstract
BACKGROUND Amplification of the proto‐oncogene c‐myc has been identified as one of the most common genetic alterations in prostate cancer, thus making it an attractive therapeutic target. However, certain prostate cancer cells are unresponsive to c‐Myc inhibition. The purpose of this study was to test the hypothesis that effective growth inhibition in the refractory cancer cells can be achieved by blocking c‐myc along with a growth factor using a novel phosphorodiamidate morpholino antisense oligomer‐based approach. Human chorionic gonadotropin, a growth factor implicated in neoplasm, causes activation of c‐myc through a G‐protein–coupled pathway of signal transduction. METHODS In this study, the effect of inhibition of β‐hCG and c‐myc singly or in combination was evaluated in DU145 (RB −/−, p53−/−, androgen‐independent) and LNCaP (Rb+/+, p53 +/+, androgen‐sensitive) human prostate cancer cell lines and in a DU145 subcutaneous xenograft murine model. RESULTS Antisense phosphorodiamidate morpholino oligomers directed against β‐hCG and c‐myc caused a specific decrease of the target protein levels. Unlike LNCaP cells, DU145 cell growth was refractory to c‐Myc inhibition. Unresponsiveness to c‐myc inhibition in DU145 cells was overcome by targeting both β‐hCG and c‐myc genes, resulting in potentiation of the antiproliferative effect seen with inhibition of β‐hCG alone. CONCLUSIONS The inhibition of β‐hCG sensitizes prostate cancer cells to the antiproliferative effects of c‐Myc inhibition, including tumors that are refractory to c‐Myc decrease alone. Prostate 53: 200–210, 2002.