Autor segons l'article: Menendez, Javier A.; Cufi, Silvia; Oliveras-Ferraros, Cristina; Martin-Castillo, Begona; Joven, Jorge; Vellon, Luciano; Vazquez-Martin, Alejandro;
Departament: Medicina i Cirurgia
Autor/s de la URV: Joven Maried, Jorge
Paraules clau: Senescence Metformin Genome stability Cancer Autophagy Atm Ampk Aging
Resum: By activating the ataxia telangiectasia mutated (ATM)-mediated DNA Damage Response (DDR), the AMPK agonist metformin might sensitize cells against further damage, thus mimicking the precancerous stimulus that induces an intrinsic barrier against carcinogenesis. Herein, we present the new hypothesis that metformin might function as a tissue sweeper of pre-malignant cells before they gain stem cell/tumor initiating properties. Because enhanced glycolysis (the Warburg effect) plays a causal role in the gain of stem-like properties of tumor-initiating cells by protecting them from the pro-senescent effects of mitochondrial respiration-induced oxidative stress, metformin's ability to disrupt the glycolytic metabotype may generate a cellular phenotype that is metabolically protected against immortalization. The bioenergetic crisis imposed by metformin, which may involve enhanced mitochondrial biogenesis and oxidative stress, can lower the threshold for cellular senescence by pre-activating an ATM-dependent pseudo-DDR. This allows an accelerated onset of cellular senescence in response to additional oncogenic stresses. By pushing cancer cells to use oxidative phosphorylation instead of glycolysis, metformin can rescue cell surface major histocompatibility complex class I (MHC-I) expression that is downregulated by oncogenic transformation, a crucial adaptation of tumor cells to avoid the adaptive immune response by cytotoxic T-lymphocytes (CTLs). Aside from restoration of tumor immunosurveillance at the cell-autonomous level, metformin can activate a senescence-associated secretory phenotype (SASP) to reinforce senescence growth arrest, which might trigger an immune-mediated clearance of the senescent cells in a non-cell-autonomous manner. By diminishing the probability of escape from the senescence anti-tumor barrier, the net effect of metformin should be a significant decrease in the accumulation of dysfunctional, pre-malignant cells in tissues, including those with the ability to initiate tumors. As life-long or late-life removal of senescent cells has been shown to prevent or delay the onset or progression of age-related disorders, the tissue sweeper function of metformin may inhibit the malignant/metastatic progression of pre-malignant/senescent tumor cells and increase the human lifespan.
Àrees temàtiques: Odontología Nutrição Medicina veterinaria Medicina iii Medicina ii Medicina i Interdisciplinar Geriatrics & gerontology Ciências biológicas ii Ciências biológicas i Cell biology Biotecnología
Accès a la llicència d'ús: https://creativecommons.org/licenses/by/3.0/es/
ISSN: 19454589
Adreça de correu electrònic de l'autor: jorge.joven@urv.cat
Identificador de l'autor: 0000-0003-2749-4541
Data d'alta del registre: 2023-02-18
Versió de l'article dipositat: info:eu-repo/semantics/publishedVersion
Referència a l'article segons font original: Aging-Us. 3 (11): 1063-1077
Referència de l'ítem segons les normes APA: Menendez, Javier A.; Cufi, Silvia; Oliveras-Ferraros, Cristina; Martin-Castillo, Begona; Joven, Jorge; Vellon, Luciano; Vazquez-Martin, Alejandro; (2011). Metformin and the ATM DNA damage response (DDR): Accelerating the onset of stress-induced senescence to boost protection against cancer. Aging-Us, 3(11), 1063-1077. DOI: 10.18632/aging.100407
URL Document de llicència: https://repositori.urv.cat/ca/proteccio-de-dades/
Entitat: Universitat Rovira i Virgili
Any de publicació de la revista: 2011
Tipus de publicació: Journal Publications
Repositori URV