Characterization of PARP1 in hepatocellular carcinoma, and evaluation of the potential of PARP1 inhibitor olaparib in HCC treatment

Abstract

PARP1, also known as poly (ADP-ribose) polymerase 1, is an abundant nuclear protein with various functions. PARP1 is able to maintain cellular homeostasis through modulating multiple cellular processes including DNA repair, replication, methylation and chromatin remodeling through adding poly (ADP-ribose) to downstream proteins, known as PARylation. In addition, PARP1 can transcriptionally regulate tumor growth and progression. In recent years, inhibitors targeting PARP1 have been investigated and been proved to be effective against several types of cancers. Among these inhibitors of PARP1, olaparib, which can effectively treat breast cancer, has drawn us attention to the treatment of HCC. In brief, our studies focused on the drug potential of olaparib in treatment of HCC. Firstly, the expression level of PARP1 in HCC tumor tissues and matched non-tumor tissues of 125 HCC patients were analyzed by quantitative PCR. The results indicated that PARP1 was up-regulated in over half of cases with 4-fold change and a significant difference was observed for overall survival (p=0.028). Meanwhile, in vitro studies also indicated that olaparib treatment could inhibit HCC tumor cell growth and cell differentiation, exerting similar or more promising effects than shRNA-mediated knockdown of PARP1. Moreover, olaparib alone could suppress tumor growth at 50 mg/kg in PLC8024 and HepG2 cell lines in vivo. Recent studies have reported that PARP1 could regulate various differentiation-related genes through the opening of promoter chromatin. With 5-day treatment of 50μM olaparib, differentiation-related genes including oct4, sox2 and c-myc were down-regulated significantly both in mRNA and protein levels. MNase protection assay studies demonstrated that olaparib could inhibit the opening of promoter chromatin of oct4, sox2 and c-myc. In addition, we also combined olaparib with sorafenib to treat mice with various combination in vivo and found that olaparib could enhance sorafenib drug potency. In conclusion, the PARP1 inhibitor olaparib alone could inhibit HCC tumor cell growth and cell differentiation and it could also enhance sorafenib drug potency and induce apoptosis, therefore providing a novel way for HCC treatment.