Cisplatin-resistance and aggressiveness are enhanced by a highly stable endothelin-converting enzyme-1c in lung cancer cells

Sep 21, 2026

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Lung cancer remains the leading cause of cancer mortality, with high endothelin-1 (ET-1) signaling involving its receptor ETA R and the activating enzyme endothelin-converting enzyme-1 (ECE-1). ECE-1 has four isoforms differing in the cytoplasmic N-terminus; phosphorylation by CK2 stabilizes the ECE-1c isoform and is linked to increased invasiveness in other cancers. This study tests whether Lys-6 regulates ECE-1c stability, cancer stem cell–like traits, and aggressiveness in non–small cell lung cancer cells.

LanguageEnglish

CategoryResearch & Report

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Abstract

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Methods

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Introduction

Almarza etal. Biological Research (2024) 57:74 Biological Research [https://doi.org/10.1186/s40659-024-00551-9](https://doi.org/10.1186/s40659-024-00551-9) RESEARCH ARTICLE Open Access Cisplatin-resistance and aggressiveness are enhanced by a highly stable endothelinconverting enzyme-1c in lung cancer cells Cristopher Almarza 1, Karla Villalobos-Nova 1, María A. Toro 1, Manuel González 1, Ignacio Niechi2, David A. Brown-Brown2, Rodrigo A. López-Muñoz3, Eduardo Silva-Pavez4, Belén Gaete-Ramírez5, Manuel Varas-Godoy5, Verónica A. Burzio6, Lilian Jara7, Francisco Aguayo8 and Julio C. Tapia 1,9* Abstract Background Lung cancer constitutes the leading cause of cancer mortality. High levels of endothelin-1 (ET-1), its cognate receptor ETA R and its activating enzyme, the endothelin-converting enzyme-1 (ECE-1), have been reported in several cancer types, including lung cancer. ECE-1 comprises four isoforms, which only differ in their cytoplasmic N-terminus. Protein kinase CK2 phosphorylates the N-terminus of isoform ECE-1c, increasing its stability and leading to enhanced invasiveness in glioblastoma and colorectal cancer cells, which is believed to be mediated by the amino acid residue Lys-6, a conserved putative ubiquitination site neighboring the CK2-phosphorylated residues Ser-18 and Ser-20 . Whether Lys-6 is linked to the acquisition of a cancer stem cell (CSC)-like phenotype and aggressiveness inhuman non–small cell lung cancer (NSCLC) cells has not been studied. Methods In order to establish the role of Lys-6 in the stability of ECE-1c and its involvement in lung cancer aggressiveness, we mutated this residue to a non-ubiquitinable arginine and constitutively expressed the wild-type (ECE-1cWT) and mutant (ECE-1cK6R) proteins in A549 and H1299 human NSCLC cells by lentiviral transduction. We determined the protein stability of these clones alone or in the presence ofthe CK2 inhibitor sil mitasertib, compared to ECE-1cWT and mock-transduced cells. In addition, the concentration of secreted ET-1 in the growth media was determined by ELISA. Expression of stemness genes were determined by Western blot and RT-qPCR. Chemoresistance to cisplatin was studied by MTS viability assay. Migration and invasion were measured through transwell and Matrigel assays, respectively, and the side-population was determined using flow cytometry. Results ECE-1cK6R displayed higher stability in NSCLC cells compared to ECE-1cWT-expressing cells, but ET-1 secreted levels showed no difference up to 48 h. Most importantly, ECE-1cK6R promoted expression of the stemness genes c-Myc, Sox-2, Oct-4, CD44 and CD133, which enhance cellular self-renewal capability. Also, the ECE-1cK6R-expressing cells showed higher cisplatin chemoresistance, correlating with an augmented side-population abundance due to the increased expression of the ABCG2 efflux pump. Finally, the ECE-1cK6R-expressing cells showed enhanced invasiveness, which correlated with the regulated expression of known EMT markers. *Correspondence: Julio C. Tapia [jtapiapineda@uchile.cl](jtapiapineda@uchile.cl) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this lic

FAQs

What question does the study address about ECE-1c in lung cancer?

The study investigates whether Lys-6 in ECE-1c controls its stability and contributes to cancer stem cell–like phenotype and aggressiveness in non–small cell lung cancer cells.

How did the researchers test the role of Lys-6?

They mutated Lys-6 to a non-ubiquitinable arginine and expressed wild-type and mutant ECE-1c proteins in A549 and H1299 NSCLC cells using lentiviral transduction.

What main effects did the Lys-6 mutant (ECE-1cK6R) show?

ECE-1cK6R increased ECE-1c stability, promoted stemness gene expression, enhanced cisplatin chemoresistance, and increased invasiveness, associated with EMT marker regulation and higher side-population via ABCG2 efflux.

Sep 21, 2026

Uploaded by Skyler