iNOS-Produced Nitric Oxide from Cancer Cells as an Intermediate of Stemness Regulation by PARP-1 in Colorectal Cancer.

Abstract

PARP-1 has been linked to the progression of several types of cancer. We have recently reported that PARP-1 influences tumor progression in CRC through the regulation of CSCs in a p53-dependent manner. In this study, we propose that nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) could act as a mediator. We evaluated the expression of iNOS in a cohort of patients previously used to analyze the effects of PARP-1 on CRC in relation to p53 status. We also developed an in vitro model in which PARP-1 was stably overexpressed. In CRC patients, iNOS expression correlated with the differentiation grade, and with a high expression of CSC markers, although only in wild-type p53 tumors, as previously found for PARP-1. In vitro, overexpression of PARP-1 induced increased growth and stemness in wild-type p53 cells, while exerting the opposite effect on mutated ones, as expected. Treatment with 1400 W, a selective inhibitor of iNOS, or gene silencing of the gene counteracted the effects of PARP-1 in both p53 wild-type and p53 mutated cells. Given that the development of resistance has been demonstrated after treatment with PARP-1 inhibitors, iNOS could be considered a new therapeutic target in CRC, although only in patients with wild-type p53 tumors.