The aminobisphohonate zoledronic acid (Zol) targets many cancer types, but the mechanism of its anti-tumor activity is not fully understood. Here, employing melanoma model, we show selective toxicity of Zol toward those melanoma cell variants, that exhibit accelerated store-operated Ca2+-influx (SOC), over-activation of PKB/Akt and increased steady-state activity of the NFAT2 transcription factor. Thus, in highly malignant B16BL6-8 and JB/RH1 murine and the BRaf blocker PLX4720-resistant GA-PLXR human melanoma cells, Zol retarded serum-independent growth and enhanced apoptosis triggered by serum withdrawal through attenuation of the SOC, down-regulation of PKB/Akt and inactivation of NFAT2. Direct targeting of NFAT2 or SOC with shRNAs against NFAT2 or Stim1, respectively, was cytotoxic by itself, indicating the crucial role of the SOC/NFAT2 pathway in protecting malignant cells from apoptosis. In this pathway, robust SOC response was coupled to NFAT2 in a PKB/Akt-GSK3b axis, since its blockade with the PI-3 kinase antagonist LY294002 or the dominant-negative PKB/Akt mutant was sufficient to inhibit NFAT2 by reactivating GSK3b, whereas SOC blockade by silencing Stim1 inhibited both PKB/Akt and NFAT2. Remarkably, Zol did not alter growth and survival of non-malignant Kb30 murine and PLX4720-susceptible GA human melanoma lines that, consistent with our hypothesis, displayed attenuated SOC, PKB/Akt and NFAT2 activities. Furthermore, Zol, administered at the doses of 0.1 and 1 mg/kg/tiw to the B16BL6-8 and GA-PLXR cell-engrafted mice, significantly retarded tumor development. Together, the results imply the potential of Zol against malignancies, driven by accelerated tumor-promoting Ca2+ signaling, and, particularly, melanoma tumors, resistant to pharmacological inhibition of BRaf.
