Better Therapeutic Target to Enhance Cisplatin Sensitivity in Cervical Cancer: PARP-1 or β-catenin
Author(s): Minakshi Mann, Shyam S Chauhan, Neerja Bhatla, Sunesh Kumar, Sameer Bakhshi, Ritu Gupta, Sandeep Mathur, Lalit Kumar
Development of resistance to cisplatin (CDDP) is a major bottleneck to treat cancer with CDDP, including cervical cancer (CC). We have recently shown that PARP-1 inhibition targets β-catenin signaling and enhance CDDP sensitivity in cervical cancer. This indicates that β-catenin itself could serve as an absolute target to potentiate CDDP cytotoxicity. So, we determined the effect of β-catenin inhibition using JW74 either alone or in combination CDDP using CC cell lines on cell vaibility, apoptosis, cell cycle progression, proliferation, invasion and metastasis, clonogenecity. However, unexpectedly β-catenin inhibitor JW74 failed to significantly enhance CDDP- cytotoxicity in both the cell lines. Since PARP-1 inhibitors inhibited β-catenin also, as determined through our previous work, so, we evaluated effect of JW74 mediated β-catenin inhibition on PARP-1 expression level inside cell. Intriguingly, we found that JW74 treatment enhanced PARP-1 expression as determined through western blotting. Increased PARP-1 serves responsible for CDDP resistance, thereby this seems stands responsible limiting our hypothesis. Further to confirm this, PARP-1 inhibitor PJ34 was added to a combination of JW74+CDDP and this significantly reduced cell survival and proliferation, enhanced cell death and decreased invasion and migration, hence enhanced CDDP sensitivity in CC cells. PJ34 with CDDP served as a better combination to increase caspase-3/7 cleavage, hence apoptosis, than combination of JW74 and CDDP; with PJ34 itself being less toxic to cells. Also PARP-1 expression was determined in human cervical cancer tissue sample at base level and compared to normal tissue sample. PARP-1 expression was significantly enhanced in human cervix cancer tumor samples. In summary, β-catenin inhibition increases PARP-1 expression, thereby, limits ability of β -catenin inhibitors to enhance CDDP cytotoxicity. Enhanced PARP-1 expression in cervix cancer tissue samples shows feasibility of using PARP-1 inhibitors in cervical cancer treatment.