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

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

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...

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Main Authors: María del Moral-Martinez, Paula Sánchez-Uceta, Ruben Clemente-Gonzalez, Sara Moreno-SanJuan, Jose D. Puentes-Pardo, Huda Khaldy, David Lopez-Perez, Javier Arnedo, Jorge Casado, Luis Martínez-Heredia, Angel Carazo, Josefa León
Format: Article
Language:English
Published: MDPI AG 2025-01-01
Series:Biomolecules
Subjects:
colorectal cancer (CRC)
PARP-1
iNOS
cancer stem cells (CSCs)
Online Access:https://www.mdpi.com/2218-273X/15/1/125
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Summary: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.
ISSN:2218-273X

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