Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53
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AuthorRíos Arrabal, Sandra; Puentes Pardo, José David; Moreno San Juan, Sara; Casado, Jorge; García Costela, María; Escudero Feliú, Julia; Verbeni, Michela; Cano Gutiérrez, Carlos; González Puga, María Cristina; Martín-Lagos Maldonado, Alicia; Carazo Gallego, Ángel; León López, Josefa
Colorectal cancerCancer stem cellsHeme oxygenase-1Endothelin-1Endothelin converting enzyme-1Bosentan
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
SponsorshipInstituto de Salud Carlos IIIFEDER (PI18/01947); MINECO grant (DPI2017-84439-R); Nicolás Monardes Program from the Andalusian Health Service (C-0033-2015); FPU2019 fellowship (FPU19/02269) from the Ministerio de Ciencia, Innovación y Universidades (Spain)
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.