PARP-1 inhibitor modulate β-catenin signaling to enhance cisplatin sensitivity in cancer cervix.

Abstract

Cisplatin is a keystone for treatment of both recurring and locally advanced cervical cancer. However toxic side effects and acquired resistance limits its efficacy. Enhanced DNA repair is one of the mechanisms through which cancer cells acquire cisplatin resistance. Inhibitors of PARP, which is a DNA damage repair enzyme, have been approved for use in BRCA mutated cancers like breast and ovary cancer. However little is known about the therapeutic efficacy of PARP inhibitors in cervical cancer, either as a single agent or in combination with cisplatin. We hypothesized that PARP-1 inhibition might improve the sensitivity of cervical cancer cells to cisplatin by diminishing DNA repair. To ascertain this, we determined effect of PARP-1 inhibition on cisplatin cytotoxicity in HeLa and SiHa cell lines. Combination of cisplatin with PJ34, a phenanthridinone-derived PARP-1 inhibitor, augmented cisplatin toxicity in vitro by decreasing cell proliferation, enhancing cell cycle block and cell death, and decreasing invasion and metastasis, when compared with either of the single agent alone. We further show that PARP-1 inhibition inhibited β-catenin signaling and its downstream components such as c-Myc, cyclin D1 and MMPs indicating a possible link between single strand base damage repair and WNT signaling. In conclusion, PARP-1 inhibition might augment cisplatin cytotoxicity in cervical cancer cells by modulating β-catenin signaling pathway. Combining PARP-1 inhibitors with cisplatin might be a promising approach to overcome cisplatin resistance and to achieve a better therapeutic effect.