ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress

Autophagy is a highly conserved intracellular process that preserves cellular homeostasis by mediating the lysosomal degradation of virtually any component of the cytoplasm. Autophagy is a key instrument of cellular response to several stresses, including endoplasmic reticulum (ER) stress. Cancer ce...

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Autores principales: Gámez-García, Andrés, Bolinaga-Ayala, Idoia, Yoldi, Guillermo, Espinosa-Gil, Sergio, Diéguez-Martínez, Nora, Megías-Roda, Elisabet, Muñoz-Guardiola, Pau, Lizcano, Jose M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600073/
https://www.ncbi.nlm.nih.gov/pubmed/34805151
http://dx.doi.org/10.3389/fcell.2021.742049
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author Gámez-García, Andrés
Bolinaga-Ayala, Idoia
Yoldi, Guillermo
Espinosa-Gil, Sergio
Diéguez-Martínez, Nora
Megías-Roda, Elisabet
Muñoz-Guardiola, Pau
Lizcano, Jose M.
author_facet Gámez-García, Andrés
Bolinaga-Ayala, Idoia
Yoldi, Guillermo
Espinosa-Gil, Sergio
Diéguez-Martínez, Nora
Megías-Roda, Elisabet
Muñoz-Guardiola, Pau
Lizcano, Jose M.
author_sort Gámez-García, Andrés
collection PubMed
description Autophagy is a highly conserved intracellular process that preserves cellular homeostasis by mediating the lysosomal degradation of virtually any component of the cytoplasm. Autophagy is a key instrument of cellular response to several stresses, including endoplasmic reticulum (ER) stress. Cancer cells have developed high dependency on autophagy to overcome the hostile tumor microenvironment. Thus, pharmacological activation or inhibition of autophagy is emerging as a novel antitumor strategy. ERK5 is a novel member of the MAP kinase family that is activated in response to growth factors and different forms of stress. Recent work has pointed ERK5 as a major player controlling cancer cell proliferation and survival. Therefore small-molecule inhibitors of ERK5 have shown promising therapeutic potential in different cancer models. Here, we report for the first time ERK5 as a negative regulator of autophagy. Thus, ERK5 inhibition or silencing induced autophagy in a panel of human cancer cell lines with different mutation patterns. As reported previously, ERK5 inhibitors (ERK5i) induced apoptotic cancer cell death. Importantly, we found that autophagy mediates the cytotoxic effect of ERK5i, since ATG5ˉ(/)ˉ autophagy-deficient cells viability was not affected by these compounds. Mechanistically, ERK5i stimulated autophagic flux independently of the canonical regulators AMPK or mTORC1. Moreover, ERK5 inhibition resulted in ER stress and activation of the Unfolded Protein Response (UPR) pathways. Specifically, ERK5i induced expression of the ER luminal chaperone BiP (a hallmark of ER stress), the UPR markers CHOP and ATF4, and the spliced form of XBP1. Pharmacological inhibition of UPR with chemical chaperone TUDC, or ATF4 silencing, resulted in impaired ERK5i-mediated UPR, autophagy and cytotoxicity. Overall, our results suggest that ERK5 inhibition induces autophagy-mediated cancer cell death by activating ER stress. Since ERK5 inhibition sensitizes cancer cells and tumors to chemotherapy, future work will determine the relevance of UPR and autophagy in the combined use of chemotherapy and ERK5i to tackle Cancer.
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spelling pubmed-86000732021-11-19 ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress Gámez-García, Andrés Bolinaga-Ayala, Idoia Yoldi, Guillermo Espinosa-Gil, Sergio Diéguez-Martínez, Nora Megías-Roda, Elisabet Muñoz-Guardiola, Pau Lizcano, Jose M. Front Cell Dev Biol Cell and Developmental Biology Autophagy is a highly conserved intracellular process that preserves cellular homeostasis by mediating the lysosomal degradation of virtually any component of the cytoplasm. Autophagy is a key instrument of cellular response to several stresses, including endoplasmic reticulum (ER) stress. Cancer cells have developed high dependency on autophagy to overcome the hostile tumor microenvironment. Thus, pharmacological activation or inhibition of autophagy is emerging as a novel antitumor strategy. ERK5 is a novel member of the MAP kinase family that is activated in response to growth factors and different forms of stress. Recent work has pointed ERK5 as a major player controlling cancer cell proliferation and survival. Therefore small-molecule inhibitors of ERK5 have shown promising therapeutic potential in different cancer models. Here, we report for the first time ERK5 as a negative regulator of autophagy. Thus, ERK5 inhibition or silencing induced autophagy in a panel of human cancer cell lines with different mutation patterns. As reported previously, ERK5 inhibitors (ERK5i) induced apoptotic cancer cell death. Importantly, we found that autophagy mediates the cytotoxic effect of ERK5i, since ATG5ˉ(/)ˉ autophagy-deficient cells viability was not affected by these compounds. Mechanistically, ERK5i stimulated autophagic flux independently of the canonical regulators AMPK or mTORC1. Moreover, ERK5 inhibition resulted in ER stress and activation of the Unfolded Protein Response (UPR) pathways. Specifically, ERK5i induced expression of the ER luminal chaperone BiP (a hallmark of ER stress), the UPR markers CHOP and ATF4, and the spliced form of XBP1. Pharmacological inhibition of UPR with chemical chaperone TUDC, or ATF4 silencing, resulted in impaired ERK5i-mediated UPR, autophagy and cytotoxicity. Overall, our results suggest that ERK5 inhibition induces autophagy-mediated cancer cell death by activating ER stress. Since ERK5 inhibition sensitizes cancer cells and tumors to chemotherapy, future work will determine the relevance of UPR and autophagy in the combined use of chemotherapy and ERK5i to tackle Cancer. Frontiers Media S.A. 2021-11-04 /pmc/articles/PMC8600073/ /pubmed/34805151 http://dx.doi.org/10.3389/fcell.2021.742049 Text en Copyright © 2021 Gámez-García, Bolinaga-Ayala, Yoldi, Espinosa-Gil, Diéguez-Martínez, Megías-Roda, Muñoz-Guardiola and Lizcano. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Gámez-García, Andrés
Bolinaga-Ayala, Idoia
Yoldi, Guillermo
Espinosa-Gil, Sergio
Diéguez-Martínez, Nora
Megías-Roda, Elisabet
Muñoz-Guardiola, Pau
Lizcano, Jose M.
ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress
title ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress
title_full ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress
title_fullStr ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress
title_full_unstemmed ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress
title_short ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress
title_sort erk5 inhibition induces autophagy-mediated cancer cell death by activating er stress
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600073/
https://www.ncbi.nlm.nih.gov/pubmed/34805151
http://dx.doi.org/10.3389/fcell.2021.742049
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