Abstract
PARP1 trapping at DNA lesion by pharmacological inhibitors has been exploited in several cancers exhibiting defects in DNA repair mechanisms. PARP1 hyperactivation is involved in therapeutic resistance in multiple cancers. The role of PARP1 in cervical cancer (CC) resistance and implication of PARP inhibitor is yet to be elucidated. Our data demonstrates significantly higher expression of PARP1 in primary cervical tumors and CC cell lines SiHa and ME180. Upon cisplatin treatment CC cells display significant overexpression of PARP1 and its hyperactivation. PARP inhibitor olaparib shows significant anti-proliferative effect on CC cells and drive loss of clonogenic survival and enhanced cell death in combination with cisplatin. PARP inhibited cells show delay in resolution of γH2A.X foci and prolonged late S and G2-M phase arrest resulting in apoptosis. Further, PARP inhibition disrupts the localization of base excision repair (BER) effector XRCC1 and non-homologous end joining (NHEJ) proteins Ku80 and XRCC4. Due to disrupted relocation of repair factors, cisplatin induced stalled replication forks collapse and convert into double strand breaks (DSBs). Interestingly, PARP inhibition also shows anti-migratory and anti-invasive properties in CC cells, increases anchorage independent cell death and induces anoikis. Collectively, our data demonstrates therapeutic potential of PARP inhibitor in cervical cancer.
Highlights
Among all the 17 members of PARP family, PARP1 is one of the most abundant proteins which is involved in regulation of transcriptional control, maintenance of genomic integrity, DNA repair and regulation of apoptotic and survival balance in cells[1,2]
PARP1 trapping at damaged DNA strand inhibits the recruitment of DNA repair enzymes at the site leading to creation of persistent double strand breaks (DSBs) in DNA which is more lethal compared with depletion of PARP protein[25]
Overexpression of PARP in cisplatin treated cells shows formation of smaller PAR polymers in early treatment which gradually increases with the increasing duration or the drug concentration and subsequently it allowed us to implicate the action of olaparib, i.e., trapping of more PARP molecules in cisplatin treated cells
Summary
Among all the 17 members of PARP family, PARP1 is one of the most abundant proteins which is involved in regulation of transcriptional control, maintenance of genomic integrity, DNA repair and regulation of apoptotic and survival balance in cells[1,2]. In past 4 decades several potent PARP inhibitors have been discovered and clinically investigated as chemotherapeutic agent for the treatment of cancers with inherent defect in their DNA repair pathways[4]. Several PARP inhibitors including Olaparib (AZD2281), Niraparib (MK-4827), Veliparib and BMN673 have been identified as potential chemotherapeutic agents. These pharmacological inhibitors have shown antitumor activity alone or in combination with platinum based therapeutic agents in several cancers with DNA repair defects including ovarian[5,6,7,8] and breast cancers[7,8,9]. Our results suggest that PARP inhibition by olaparib and its combination with cisplatin has profound anticancer effect and anti-metastatic effect and may be used as therapeutic strategy in treatment of advanced cervical carcinoma
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