Molecular mechanism of bone metastasis in prostate cancer

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Bisphosphonates are well established for the management of cancer-induced skeletal complications.Recent studies suggest that bisphosphonates promote apoptosis of cancer cells as well as osteoclasts in bone metastatic sites.In the present study, to determine the direct effects of bisphosphonate on prostate cancer cells, we examined the effects of minodronate on prostatic cancer cell growth and the expression of apoptosis related proteins and osteoclastogenic factors.PC-3, DU 145 and LNCaP cells were treated with amino-bisphosphonate minodronate.Then proliferation, apoptosis and expression of bcl-2, bax, poly(ADP)-ribose polymerase(PARP), caspase-3, receptor activator of nuclear factor-kB ligand(RANKL), osteoprotegerin(OPG), matrix metalloproteinases-2(MMP-2), and parathyroid hormone related protein(PTHrP)were assessed. The proliferation of LNCaP, DU145 and PC-3 cells were inhibited by minodronate.DNA fragmentation and TUNEL positive nuclei were observed in minodronate treated PC-3 cells.Minodronate decreased bax expression and induced bcl-2 expression, caspase-3 activity and degradation of PARP in DU145 and PC-3 cells. Minodronate decreased expression of RANKL, PTHrP and MMP-2 in PC-3 cells.Antitumor effect of a new bisphosphonate, YM-529 was tested using a mouse model of bone tumor formation created by intratibial injection of hormone refractory LNCaP-SF cells.Antitumor effect of YM-529 on bone tumor formation was evident in a dose-dependent manner as no new osteoid formation was seen in mice treated with YM-529, while tumor cell invasion into bone matrix was remarkable in control mice.Our results suggest that bisphosphonate not only directly promotes prostate cancer cell apoptosis but also decreases pro-osteoclasfic gene expression in prostate cancer cells, and has the potential of an antitumor agent against hormone refractory prostate cancer.