PARG Inhibition Modulates Viability, Clonogenicity and Migration of Breast Cancer Cells Response to Radiotherapy

Background Targeting DNA repair through inhibition of poly (ADP-ribose) glycohydrolase (PARG) enzyme is a promising strategy to modulate cancer resistance to traditional therapy. In the present work, we evaluated the possible modifying effect of PARG inhibition in breast cancer cell lines’ response to DNA damage-induced by radiotherapy. Methods Breast cancer cell lines (MCF-7 and MDA-MB-231) were exposed to different doses of ionizing radiation (IR) either with or without PDD00017273, a PARG inhibitor, and evaluated cellular response after 48 hours. MTT assay was utilized to evaluate cellular viability, clonogenic assay and migration assay were performed, relative gene expression of PARG and apoptosis inducing factor (AIF) was evaluated using realtime PCR, and protein expression of PARG was detected using immunostaining. Results Our findings showed that PARGi prior to irradiation treatment significantly increased PARG expression on both gene and protein levels, which was accompanied with a significant drop in cellular viability in both cell lines compared to IR alone. These results were further confirmed by the upregulated expression of AIF gene. Cellular clonogenicity and migration have declined significantly in cells treated with PARGi + IR combination rather than IR alone. Conclusions Our study highlights the effect of PARGi in radio-sensitizing breast cancer cell lines, emphasizing its role in undermining the mechanisms of repairing DNA and increasing their sensitivity to IR.