Bisphosphonates are expected to be efficacious to prevent the growth of metastatic cancer in bone tissue. Bone metastases often occur in patients with various cancers, such as breast, lung and prostate cancer. Bcl-2 is a potent antiapoptotic protein and its expression is known to be closely related to its function. In this study, to investigate the effect of bisphosphonates on cancer cells, we focused on bcl-2 expression in bisphosphonate-treated prostate cancer cells. First, we observed that bcl-2 mRNA expression in PC-3 was significantly inhibited to 12% of the control level by treatment with 100 microM pamidronate for 12h. Inhibition was seen in cells treated with nitrogen-containing bisphosphonates, which have the ability to inhibit isoprenoid biosynthesis via the mevalonate pathway, but not in non-nitrogen-containing etidronate. Simultaneous treatment with geranylgeraniol, an intermediate of the mevalonate pathway, significantly blocked inhibition by pamidronate, and treatment with geranylgeranyl transferase inhibitor GGTI-286 also suppressed bcl-2 mRNA expression. Furthermore, pamidronate inhibited the translocation of Rap1 protein to the membrane fraction, suggesting that a change in posttranslational modification of Rap1 occurred in treated cells. Finally, knockdown of Rap1 by siRNA resulted in the inhibition of bcl-2 expression. These results strongly indicate that bcl-2 reduction in bisphosphonate-treated PC-3 cells is dependent on inhibition of the mevalonate pathway. The inhibitory effect of bisphosphonates on bcl-2 expression shown in prostate cancer cell line should be tested in animal experiments and clinical studies.
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