ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress
| Autor: | Andrés Gámez-García, Idoia Bolinaga-Ayala, Guillermo Yoldi, Sergio Espinosa-Gil, Nora Diéguez-Martínez, Elisabet Megías-Roda, Pau Muñoz-Guardiola, Jose M. Lizcano |
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| Přispěvatelé: | Institut Català de la Salut, [Gámez-García A, Yoldi G] Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Bolinaga-Ayala I, Espinosa-Gil S, Diéguez-Martínez N, Megías-Roda E, Lizcano JM] Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain. Grup de Recerca en Proteïnes Kinases i Càncer, Vall Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
fenómenos fisiológicos celulares::muerte celular::autofagia [FENÓMENOS Y PROCESOS]
XBP1 Cell Physiological Phenomena::Cell Death::Autophagy [PHENOMENA AND PROCESSES] QH301-705.5 Cellular homeostasis Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] mTORC1 MAPK signal pathway Other subheadings::Other subheadings::/drug therapy [Other subheadings] Otros calificadores::/efectos de los fármacos [Otros calificadores] neoplasias [ENFERMEDADES] Cell and Developmental Biology Autofàgia medicine Biology (General) Other subheadings::/drug effects [Other subheadings] cancer cell survival Original Research UPR – unfolded protein response Chemistry Endoplasmic reticulum Càncer - Tractament Autophagy ERK5 kinase apoptosis Cancer Cell Biology medicine.disease antitumor drug endoplamic reticulum stress Cell biology autopaghy Neoplasms [DISEASES] Cancer cell Unfolded protein response Cèl·lules canceroses Developmental Biology |
| Zdroj: | Scientia Frontiers in Cell and Developmental Biology Frontiers in Cell and Developmental Biology, Vol 9 (2021) |
| ISSN: | 2296-634X |
| DOI: | 10.3389/fcell.2021.742049 |
| Popis: | ERK5 kinase; Antitumor drug; Apoptosis Kinasa ERK5; Medicament antitumoral; Apoptosi Quinasa ERK5; Medicamento antitumoral; Apoptosis 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. This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO, grant SAF2015-64237-R), the Spanish Ministry of Science and Innovation (Grant PID2019-107561RB-I00), and cofounded by the European Regional Development Fund (ERDF). |
| Databáze: | OpenAIRE |
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