Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53
Heme oxygenase-1 (HO-1) is an antioxidant protein implicated in tumor progression, metastasis, and resistance to therapy. Elevated HO-1 expression is associated with stemness in several types of cancer, although this aspect has not yet been studied in colorectal cancer (CRC). Using an in vitro model...
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MDPI AG
2021-06-01
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| Series: | Journal of Personalized Medicine |
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| Online Access: | https://www.mdpi.com/2075-4426/11/6/509 |
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| author | Sandra Ríos-Arrabal Jose D. Puentes-Pardo Sara Moreno-SanJuan Ágata Szuba Jorge Casado María García-Costela Julia Escudero-Feliu Michela Verbeni Carlos Cano Cristina González-Puga Alicia Martín-Lagos Maldonado Ángel Carazo Josefa León |
| author_facet | Sandra Ríos-Arrabal Jose D. Puentes-Pardo Sara Moreno-SanJuan Ágata Szuba Jorge Casado María García-Costela Julia Escudero-Feliu Michela Verbeni Carlos Cano Cristina González-Puga Alicia Martín-Lagos Maldonado Ángel Carazo Josefa León |
| author_sort | Sandra Ríos-Arrabal |
| collection | DOAJ |
| description | Heme oxygenase-1 (HO-1) is an antioxidant protein implicated in tumor progression, metastasis, and resistance to therapy. Elevated HO-1 expression is associated with stemness in several types of cancer, although this aspect has not yet been studied in colorectal cancer (CRC). Using an in vitro model, we demonstrated that HO-1 overexpression regulates stemness and resistance to 5-FU treatment, regardless of p53. In samples from CRC patients, HO-1 and endothelin converting enzyme-1 (ECE-1) expression correlated significantly, and p53 had no influence on this result. Carbon monoxide (CO) activated the ECE-1/endothelin-1 (ET-1) pathway, which could account for the protumoral effects of HO-1 in p53 wild-type cells, as demonstrated after treatment with bosentan (an antagonist of both ETRA and ETRB endothelin-1 receptors). Surprisingly, in cells with a non-active p53 or a mutated p53 with gain-of-function, ECE-1-produced ET-1 acted as a protective molecule, since treatment with bosentan led to increased efficiency for spheres formation and percentage of cancer stem cells (CSCs) markers. In these cells, HO-1 could activate or inactivate certain unknown routes that could induce these contrary responses after treatment with bosentan in our cell model. However more research is warranted to confirm these results. Patients carrying tumors with a high expression of both HO-1 and ECE-1 and a non-wild-type p53 should be considered for HO-1 based-therapies instead of ET-1 antagonists-based ones. |
| first_indexed | 2024-03-10T10:43:32Z |
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| institution | Directory Open Access Journal |
| issn | 2075-4426 |
| language | English |
| last_indexed | 2024-03-10T10:43:32Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
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| series | Journal of Personalized Medicine |
| spelling | doaj.art-0309f0597ff441e5ad7bd565a4567f4e2023-11-21T22:46:28ZengMDPI AGJournal of Personalized Medicine2075-44262021-06-0111650910.3390/jpm11060509Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53Sandra Ríos-Arrabal0Jose D. Puentes-Pardo1Sara Moreno-SanJuan2Ágata Szuba3Jorge Casado4María García-Costela5Julia Escudero-Feliu6Michela Verbeni7Carlos Cano8Cristina González-Puga9Alicia Martín-Lagos Maldonado10Ángel Carazo11Josefa León12Instituto 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, SpainUnidad de Gestión Clínica de Cirugía, Complejo Hospitalario de Jaén, 23007 Jaén, 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, SpainDepartamento de Ciencias de la Computación e Inteligencia Artificial, E.T.S. de Ingenierías Informática y de Telecomunicación, Universidad de Granada, 18014 Granada, SpainDepartamento de Ciencias de la Computación e Inteligencia Artificial, E.T.S. de Ingenierías Informática y de Telecomunicación, Universidad de Granada, 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, SpainInstituto de Investigación Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, SpainHeme oxygenase-1 (HO-1) is an antioxidant protein implicated in tumor progression, metastasis, and resistance to therapy. Elevated HO-1 expression is associated with stemness in several types of cancer, although this aspect has not yet been studied in colorectal cancer (CRC). Using an in vitro model, we demonstrated that HO-1 overexpression regulates stemness and resistance to 5-FU treatment, regardless of p53. In samples from CRC patients, HO-1 and endothelin converting enzyme-1 (ECE-1) expression correlated significantly, and p53 had no influence on this result. Carbon monoxide (CO) activated the ECE-1/endothelin-1 (ET-1) pathway, which could account for the protumoral effects of HO-1 in p53 wild-type cells, as demonstrated after treatment with bosentan (an antagonist of both ETRA and ETRB endothelin-1 receptors). Surprisingly, in cells with a non-active p53 or a mutated p53 with gain-of-function, ECE-1-produced ET-1 acted as a protective molecule, since treatment with bosentan led to increased efficiency for spheres formation and percentage of cancer stem cells (CSCs) markers. In these cells, HO-1 could activate or inactivate certain unknown routes that could induce these contrary responses after treatment with bosentan in our cell model. However more research is warranted to confirm these results. Patients carrying tumors with a high expression of both HO-1 and ECE-1 and a non-wild-type p53 should be considered for HO-1 based-therapies instead of ET-1 antagonists-based ones.https://www.mdpi.com/2075-4426/11/6/509colorectal cancercancer stem cellsheme oxygenase-1endothelin-1endothelin con-verting enzyme-1bosentan |
| spellingShingle | Sandra Ríos-Arrabal Jose D. Puentes-Pardo Sara Moreno-SanJuan Ágata Szuba Jorge Casado María García-Costela Julia Escudero-Feliu Michela Verbeni Carlos Cano Cristina González-Puga Alicia Martín-Lagos Maldonado Ángel Carazo Josefa León Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53 Journal of Personalized Medicine colorectal cancer cancer stem cells heme oxygenase-1 endothelin-1 endothelin con-verting enzyme-1 bosentan |
| title | Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53 |
| title_full | Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53 |
| title_fullStr | Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53 |
| title_full_unstemmed | Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53 |
| title_short | Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53 |
| title_sort | endothelin 1 as a mediator of heme oxygenase 1 induced stemness in colorectal cancer influence of p53 |
| topic | colorectal cancer cancer stem cells heme oxygenase-1 endothelin-1 endothelin con-verting enzyme-1 bosentan |
| url | https://www.mdpi.com/2075-4426/11/6/509 |
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