Author, as appears in the article.: Menendez, Javier A.; Cufi, Silvia; Oliveras-Ferraros, Cristina; Martin-Castillo, Begona; Joven, Jorge; Vellon, Luciano; Vazquez-Martin, Alejandro;

Department: Medicina i Cirurgia

URV's Author/s: Joven Maried, Jorge

Keywords: Senescence Metformin Genome stability Cancer Autophagy Atm Ampk Aging

Abstract: 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.

Thematic Areas: Odontología Nutrição Medicina veterinaria Medicina iii Medicina ii Medicina i Interdisciplinar Geriatrics & gerontology Ciências biológicas ii Ciências biológicas i Cell biology Biotecnología

licence for use: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 19454589

Author's mail: jorge.joven@urv.cat

Author identifier: 0000-0003-2749-4541

Record's date: 2023-02-18

Papper version: info:eu-repo/semantics/publishedVersion

Link to the original source: https://www.aging-us.com/article/100407

Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/

Papper original source: Aging-Us. 3 (11): 1063-1077

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

Article's DOI: 10.18632/aging.100407

Entity: Universitat Rovira i Virgili

Journal publication year: 2011

Publication Type: Journal Publications