Zoledronic acid induces anti-cancer effects on prostate cancer cells through the modulation of the angiogenesis associated CYR61 and the androgen-differentiation associated NDRG-1 genes

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21079 Background: Aminobisphosphonates (ABPs) has a definite direct anti-tumour activity but a limited activity in vivo. Their molecular targets are still not completely defined. Therefore, we have studied the effects of zoledronic acid (ZOL) addition to prostate cancer PC3 cells on gene expression profile. Methods: We have treated PC3 cells with 100 μM ZOL for 24 hours, extracted mRNAs and probed on Affimetrix HG-U133. Thereafter, we have identified down modulated and upregulated genes and checked for modulation of mRNA with RT PCR and of the relative encoded proteins with western blotting. Results: We have found 6 down modulated and 32 upregulated genes. We have focused our attention on NDRG1 associated to the androgen-differentiation and on Cysteine rich 61 (CYR61) involved in the regulation of proliferation and angiogenesis. NDRG1 mRNA was up-regulated and CYR61 mRNA was downregulated by ZOL in a dose-dependent manner. Similar effects were observed at protein product levels with an about 2-fold change recorded already in cells treated with 50 μM ZOL. Interestingly, also Gefitinib, Sorafenib and Tipifarnib used at their IC:50s could induce changes in both NDRG1 and CYR61 expression, but 50 μM ZOL was about 2-fold more potent. On the other hand, cytotoxic agents such as docetaxel did not have any effect. The addition of farnesol (FOH) or geranylgeraniol (GGOH) to ZOL-treated cells was able to counteract the effect of ZOL on CYR61 expression partially or completely, respectively. On the other hand, both FOH and GGOH had poor effect on the regulation of NDRG1 expression induced by ZOL. Conclusions: ZOL induces a strong regulation of the expression of NDRG1 and CYR61 at both mRNA and protein levels that appears to be dose-dependent and specific. CYR61 modulation seems to be more dependent from the inhibition of geranylgeranylation processes while NDRG1 changes could be at least in part independent from the inhibition of isoprenylation induced by ZOL. The study of the biological relevance of these effects on the anti-cancer effects of ZOL is ongoing with small interference RNA approaches. No significant financial relationships to disclose.