Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53

Ríos-Arrabal, Sandra; Puentes-Pardo, Jose D.; Moreno-SanJuan, Sara; Szuba, Ágata; Casado, Jorge; García-Costela, María; Escudero-Feliu, Julia; Verbeni, Michela; Cano, Carlos; González-Puga, Cristina; Martín-Lagos Maldonado, Alicia; Carazo, Ángel; León, Josefa

doi:10.3390/jpm11060509

Open AccessArticle

Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53

by

Sandra Ríos-Arrabal

^1,†,

Jose D. Puentes-Pardo

^1,2,†

,

Sara Moreno-SanJuan

^1,3,†,

Ágata Szuba

^4,†,

Jorge Casado

¹,

María García-Costela

¹,

Julia Escudero-Feliu

¹

,

Michela Verbeni

⁵

,

Carlos Cano

⁵

,

Cristina González-Puga

^1,6,

Alicia Martín-Lagos Maldonado

^1,7,

Ángel Carazo

^1,‡ and

Josefa León

^1,7,*,‡

¹

Instituto de Investigación Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain

²

Departamento de Farmacología, Facultad de Farmacia, Universidad de Granada, 18071 Granada, Spain

³

Cytometry and Microscopy Research Service, Instituto de Investigación Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain

⁴

Unidad de Gestión Clínica de Cirugía, Complejo Hospitalario de Jaén, 23007 Jaén, Spain

⁵

Departamento de Ciencias de la Computación e Inteligencia Artificial, E.T.S. de Ingenierías Informática y de Telecomunicación, Universidad de Granada, 18014 Granada, Spain

⁶

Unidad de Gestión Clínica de Cirugía, Hospital Universitario San Cecilio de Granada, 18016 Granada, Spain

⁷

Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario San Cecilio de Granada, 18016 Granada, Spain

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

These authors contributed equally to this work.

J. Pers. Med. 2021, 11(6), 509; https://doi.org/10.3390/jpm11060509

Submission received: 2 May 2021 / Revised: 26 May 2021 / Accepted: 1 June 2021 / Published: 4 June 2021

(This article belongs to the Special Issue Personalized Medicine in Oncology)

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Abstract

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.

Keywords: colorectal cancer; cancer stem cells; heme oxygenase-1; endothelin-1; endothelin con-verting enzyme-1; bosentan

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MDPI and ACS Style

Ríos-Arrabal, S.; Puentes-Pardo, J.D.; Moreno-SanJuan, S.; Szuba, Á.; Casado, J.; García-Costela, M.; Escudero-Feliu, J.; Verbeni, M.; Cano, C.; González-Puga, C.; et al. Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53. J. Pers. Med. 2021, 11, 509. https://doi.org/10.3390/jpm11060509

AMA Style

Ríos-Arrabal S, Puentes-Pardo JD, Moreno-SanJuan S, Szuba Á, Casado J, García-Costela M, Escudero-Feliu J, Verbeni M, Cano C, González-Puga C, et al. Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53. Journal of Personalized Medicine. 2021; 11(6):509. https://doi.org/10.3390/jpm11060509

Chicago/Turabian Style

Ríos-Arrabal, Sandra, Jose D. Puentes-Pardo, Sara Moreno-SanJuan, Ágata Szuba, Jorge Casado, María García-Costela, Julia Escudero-Feliu, Michela Verbeni, Carlos Cano, Cristina González-Puga, and et al. 2021. "Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53" Journal of Personalized Medicine 11, no. 6: 509. https://doi.org/10.3390/jpm11060509

APA Style

Ríos-Arrabal, S., Puentes-Pardo, J. D., Moreno-SanJuan, S., Szuba, Á., Casado, J., García-Costela, M., Escudero-Feliu, J., Verbeni, M., Cano, C., González-Puga, C., Martín-Lagos Maldonado, A., Carazo, Á., & León, J. (2021). Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53. Journal of Personalized Medicine, 11(6), 509. https://doi.org/10.3390/jpm11060509

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Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53

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