Abstract
Prostate cancer, which is a bone metastatic cancer, is the second leading cause of cancer-related death in men. There is no effective treatment for metastatic prostate cancer. Regucalcin has been shown to contribute as a suppressor in various types of human cancers. In the present study, furthermore, we investigate an involvement of regucalcin in suppression of prostate cancer. Regucalcin expression was compared in 131 primary tumor tissues and 19 metastatic tumor tissues in prostate cancer patients. Regucalcin expression in the metastatic tumor was found to be reduced as compared with that in primary tumor. The progression-free survival rate was prolonged in patients with a higher regucalcin expression. Translationally, overexpression of regucalcin in bone metastatic human prostate cancer PC-3 and DU-145 cells suppressed colony formation and cell growth in vitro. Mechanistically, overexpressed regucalcin enhanced the levels of p53, Rb, and p21, and decreased the levels of Ras, PI3 kinase, Akt, and mitogen-activated protein kinase, leading to suppression of cell growth. Furthermore, higher regucalcin expression suppressed the levels of nuclear factor-κB p65, β-catenin, and signal transducer and activator of transcription 3, which regulate a transcription activity. Cell growth was promoted by culturing with the calcium agonist Bay K 8644. This effect was blocked by overexpression of regucalcin. Notably, overexpressed regucalcin suppressed bone metastatic activity of PC-3 and DU-145 cells when cocultured with preosteoblastic or preosteoclastic cells. Regucalcin may suppress the development of human prostate cancer, suggesting that gene delivery systems in which its expression is forced may be a novel therapeutic strategy.