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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2025-01-01
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| author | 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 |
| author_facet | 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 |
| author_sort | María del Moral-Martinez |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2e778b9d284b42dbb3a541b56730a13c |
| institution | Kabale University |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-2e778b9d284b42dbb3a541b56730a13c2025-01-24T13:25:17ZengMDPI AGBiomolecules2218-273X2025-01-0115112510.3390/biom15010125iNOS-Produced Nitric Oxide from Cancer Cells as an Intermediate of Stemness Regulation by PARP-1 in Colorectal CancerMaría del Moral-Martinez0Paula Sánchez-Uceta1Ruben Clemente-Gonzalez2Sara Moreno-SanJuan3Jose D. Puentes-Pardo4Huda Khaldy5David Lopez-Perez6Javier Arnedo7Jorge Casado8Luis Martínez-Heredia9Angel Carazo10Josefa León11Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de las Nieves, 18014 Granada, SpainInstituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, SpainInstituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, SpainServicio de Microscopía y Citometría, Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, SpainInstituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, SpainServicio de Biología Fundamental, Centro de Instrumentación Científica, Universidad de Granada, 18071 Granada, SpainInstituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, SpainDepartamento de Estadística e Investigación Operativa, Universidad de Granada, 18071 Granada, SpainUnidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de las Nieves, 18014 Granada, SpainInstituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, SpainInstituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, SpainInstituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, SpainPARP-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.https://www.mdpi.com/2218-273X/15/1/125colorectal cancer (CRC)PARP-1iNOScancer stem cells (CSCs) |
| spellingShingle | 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 iNOS-Produced Nitric Oxide from Cancer Cells as an Intermediate of Stemness Regulation by PARP-1 in Colorectal Cancer Biomolecules colorectal cancer (CRC) PARP-1 iNOS cancer stem cells (CSCs) |
| title | iNOS-Produced Nitric Oxide from Cancer Cells as an Intermediate of Stemness Regulation by PARP-1 in Colorectal Cancer |
| title_full | iNOS-Produced Nitric Oxide from Cancer Cells as an Intermediate of Stemness Regulation by PARP-1 in Colorectal Cancer |
| title_fullStr | iNOS-Produced Nitric Oxide from Cancer Cells as an Intermediate of Stemness Regulation by PARP-1 in Colorectal Cancer |
| title_full_unstemmed | iNOS-Produced Nitric Oxide from Cancer Cells as an Intermediate of Stemness Regulation by PARP-1 in Colorectal Cancer |
| title_short | iNOS-Produced Nitric Oxide from Cancer Cells as an Intermediate of Stemness Regulation by PARP-1 in Colorectal Cancer |
| title_sort | inos produced nitric oxide from cancer cells as an intermediate of stemness regulation by parp 1 in colorectal cancer |
| topic | colorectal cancer (CRC) PARP-1 iNOS cancer stem cells (CSCs) |
| url | https://www.mdpi.com/2218-273X/15/1/125 |
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