Anticancer sensitivities and biological characteristics of HCT116 cells resistant to the selective poly(ADP-ribose) glycohydrolase inhibitor.

Poly(ADP-ribose) glycohydrolase (PARG) is a key enzyme involved in poly(ADP-ribose) (PAR) degradation and is considered a potential anticancer target. We previously investigated resistance mechanisms to the PARG inhibitor PDD00017273 in human colorectal cancer HCT116 cells and established an acquired PDD00017273-resistant HCT116RPDD cell line. In this study, we analyzed the protein levels of enzymes associated with PAR metabolism in both parental HCT116 cells and resistant HCT116RPDD cells using western blotting. PARG expression levels were similar between HCT116RPDD and HCT116 cells. However, the levels of PARP1 and ARH3 were reduced in HCT116RPDD cells compared to HCT116 cells. Nevertheless, intracellular PAR levels were elevated in HCT116RPDD cells. Interestingly, HCT116RPDD cells exhibited greater sensitivity to γ-ray irradiation and the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866 than the parental HCT116 cells, yet showed comparable sensitivity to 5-FU, cisplatin, and PARP inhibitors olaparib, talazoparib, and veliparib. Furthermore, we observed that HCT116RPDD cells tended to maintain slightly higher levels of intracellular NAD+/NADH and ATP compared to parental HCT116 cells. These findings suggest that cancer cells employ a mechanism to regulate NAD+ and ATP levels, thereby avoiding cell death from intracellular PAR accumulation through coordinated PARP-PARG regulation.