ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity

Autor: Alcalá, S., Sancho, P., Martinelli, P., Navarro, D., Pedrero, C., Martín-Hijano, L., Valle, S., Earl, J., Rodríguez-Serrano, M., Ruiz-Cañas, L., Rojas, K., Carrato, A., García-Bermejo, L., Fernández-Moreno, M.Á., Hermann, P.C., Sainz, B., Jr.
Přispěvatelé: Ministerio de Economía y Competitividad (España), Concern Foundation, Fundación Científica Asociación Española Contra el Cáncer, Fundación Fero, Instituto de Salud Carlos III, European Commission, German Cancer Aid, German Research Foundation, Austrian Science Fund, UAM. Departamento de Bioquímica
Rok vydání: 2020
Předmět:
0301 basic medicine
Cell Plasticity
General Physics and Astronomy
Mitochondrion
medicine.disease_cause
Oxidative Phosphorylation
Metastasis
0302 clinical medicine
Mitophagy
lcsh:Science
Cancer
Multidisciplinary
Tumor
Cancer stem cells
Biología y Biomedicina / Biología
Cancer metabolism
Metformin
Mitochondrial DNA
Mitochondria
Cell biology
Cell Transformation
Neoplastic
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Cytokines
Stem cell
Carcinoma
Pancreatic Ductal
Plasticity
Science
Oxidative phosphorylation
Biology
Article
General Biochemistry
Genetics and Molecular Biology
Cell Line
03 medical and health sciences
Pancreatic cancer
medicine
Humans
Ubiquitins
General Chemistry
medicine.disease
ISG15
Pancreatic Neoplasms
030104 developmental biology
Metabolism
lcsh:Q
RNA Editing
Cell
Carcinogenesis
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
Biblos-e Archivo: Repositorio Institucional de la UAM
Universidad Autónoma de Madrid
Nature Communications, Vol 11, Iss 1, Pp 1-17 (2020)
Biblos-e Archivo. Repositorio Institucional de la UAM
Nature Communications
Zaguán. Repositorio Digital de la Universidad de Zaragoza
Zaguán: Repositorio Digital de la Universidad de Zaragoza
Universidad de Zaragoza
ISSN: 2012-1210
Popis: Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness.
This study was supported by a Ramón y Cajal Merit Award (RYC-2012-12104) from the Ministerio de Economía y Competitividad, Spain (B.S.); a Conquer Cancer Now Grant from the Concern Foundation (Los Angeles, CA, USA) (B.S.); a Coordinated grant from the Fundación Asociación Española Contra el Cáncer (AECC, GC16173694BARB) (A.C. and B.S.); funding from The Fero Foundation (B.S.); Fondo de Investigaciones Sanitarias (FIS) grants PI15/01507 and PI18/00757 (B.S.), PI15/01715 and PI18/00267 (M.L.G-B.), PI17/00082 (P.S.) and PI15/02101 (A.C.) (all co-financed through Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”) and a Miguel Servet award (CP16/00121) (P.S.), all from the Instituto de Salud Carlos III (ISCIII), Spain; funding from the Biomedical Research Network in Cancer (CIBERONC:CB16/12/00446) for clinical sample and data collection (A.C.); a Max Eder Fellowship of the German Cancer Aid (111746) (P.C.H.); the German Research Foundation (DFG, CRC 1279 “Exploiting the human peptidome for Novel Antimicrobial and Anticancer Agents”) (P.C.H.); and the Austrian Science Fund (FWF-B27361) and Ingrid Shaker-Nessmann Foundation for Cancer Research (P.M.).
Databáze: OpenAIRE
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