Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy

SIMPLE SUMMARY: We have shown that Clear Cell Renal Cell Carcinoma (ccRCC) is prone to accumulate poly(ADPribose) due to increase in PARP-1 and decrease in PARG enzymes. Reduction of pADPr by PARP-1 inhibition or PARG overexpression disrupts renal carcinoma cell malignancy. We have shown that ccRCC is prone to accumulate poly(ADPribose) due to increase in PARP-1 and decrease in PARG enzymes. Reduction of pADPr by PARP-1 inhibition or PARG overexpression disrupts renal carcinoma cell malignancy. Transcriptome analysis linked observed phenotype with changes in gene expression levels for lipid metabolism, interferon signaling, and angiogenesis pathways along with the changes in expression of key cancer-related genes. While apoptosis level didn’t change under pADPr reduction with chemical or genetic approaches, our work supports the idea that gene expression modulation is a primary cause for observed anti-tumor effects. ABSTRACT: Poly(ADP-ribose) polymerase 1 (PARP-1) and glycohydrolase (PARG) enzymes regulate chromatin structure, transcription activation, and DNA repair by modulating poly(ADP-ribose) (pADPr) level. Interest in PARP-1 inhibitors has soared recently with the recognition of their antitumor efficacy. We have shown that the development of clear cell renal cell carcinoma (ccRCC) is associated with extreme accumulation of pADPr caused by the enhanced expression of PARP-1 and decreased PARG levels. The most severe misregulation of pADPr turnover is found in ccRCC specimens from metastatic lesions. Both, classical NAD-like and non-NAD-like PARP-1 inhibitors reduced viability and clonogenic potential of ccRCC cell lines and suppressed growth of ccRCC xenograft tumors. However, classical NAD-like PARP-1 inhibitors affected viability of normal kidney epithelial cells at high concentrations, while novel non-NAD-like PARP-1 inhibitors exhibited activity against malignant cells only. We have also utilized different approaches to reduce the pADPr level in ccRCC cells by stably overexpressing PARG and demonstrated the prominent antitumor effect of this “back-to-normal” intervention. We also generated ccRCC cell lines with stable overexpression of PARG under doxycycline induction. This genetic approach demonstrated significantly affected malignancy of ccRCC cells. Transcriptome analysis linked observed phenotype with changes in gene expression levels for lipid metabolism, interferon signaling, and angiogenesis pathways along with the changes in expression of key cancer-related genes.