Metformin lowers the threshold for stress-induced senescence: A role for the microRNA-200 family and miR-205

Cufí, Sílvia; Vázquez-Martín, Alejandro; Oliveras‐Ferraros, Cristina; Quirantes, R.; Segura‐Carretero, Antonio; Micol, Vicente; Joven, Jorge; Bosch-Barrera, Joaquim; Barco, Sonia Del; Martín-Castillo, Begoña; Vellón, Luciano; Menendez, Javier A.

doi:10.4161/cc.11.6.19665

Cited by 51 publications

(33 citation statements)

References 122 publications

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“…66,67 Moreover, low concentrations of metformin were sufficient to efficiently circumvent the stress-resistant phenotype of established iPSCs. 68 In our hands, exogenous supplementation with metformin drastically reduced both the number and the size of iPSC colonies and notably diminished the acquired expression of pluripotency markers, including alkaline phosphatase, 68 SSEA-1, OCT4 and NANOG (unpublished observations). glucose-starved microenvironment of tumors are more resistant to chemotherapy and radiation, it is reasonable to suggest that a rational combination of AMPK agonists and/or mTOR inhibitors can potentiate cytotoxic activity of current cancer treatments against tumor cells, while protecting normal cells, thus further increasing the therapeutic window.…”

Section: Cancer Metabolic Diseases and Metforminsupporting

confidence: 50%

Metformin is synthetically lethal with glucose withdrawal in cancer cells

et al. 2012

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Section: Cancer Metabolic Diseases and Metforminsupporting

confidence: 50%

Metformin is synthetically lethal with glucose withdrawal in cancer cells

et al. 2012

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“…We provide evidence that metformin lowers protein levels of p16 and/or p21 and also decreases levels of IL6, IL8, CXCL1 and CXCL2 mRNAs, all encoding critical SASP factors. A previous report found that metformin enhances cellular senescence using different cell model systems and high doses of metformin (1–5 m m ) with possible value in cancer therapy (Cufi et al ., 2012). Here, we chose a lower range of concentrations (100–500 μ m ) that reflects the physiological circulating levels of metformin in mice and in diabetic patients treated with metformin (Sum et al ., 1992).…”

Section: Discussionmentioning

confidence: 99%

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

et al. 2016

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SummaryMetformin, an oral hypoglycemic agent, has been used for decades to treat type 2 diabetes mellitus. Recent studies indicate that mice treated with metformin live longer and have fewer manifestations of age‐related chronic disease. However, the molecular mechanisms underlying this phenotype are unknown. Here, we show that metformin treatment increases the levels of the microRNA‐processing protein DICER1 in mice and in humans with diabetes mellitus. Our results indicate that metformin upregulates DICER1 through a post‐transcriptional mechanism involving the RNA‐binding protein AUF1. Treatment with metformin altered the subcellular localization of AUF1, disrupting its interaction with DICER1 mRNA and rendering DICER1 mRNA stable, allowing DICER1 to accumulate. Consistent with the role of DICER1 in the biogenesis of microRNAs, we found differential patterns of microRNA expression in mice treated with metformin or caloric restriction, two proven life‐extending interventions. Interestingly, several microRNAs previously associated with senescence and aging, including miR‐20a, miR‐34a, miR‐130a, miR‐106b, miR‐125, and let‐7c, were found elevated. In agreement with these findings, treatment with metformin decreased cellular senescence in several senescence models in a DICER1‐dependent manner. Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence‐associated secretory phenotype (SASP). These data lead us to hypothesize that changes in DICER1 levels may be important for organismal aging and to propose that interventions that upregulate DICER1 expression (e.g., metformin) may offer new pharmacotherapeutic approaches for age‐related disease.

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“…In vivo studies have shown that metformin can negatively affect the growth of human tumors even in the presence of activating mutations in the PIK3CA oncogene, another evolutionary conserved regulator of cell metabolism that converges with and impinges on the mTOR pathway. 10,[26][27][28][29][30][31][32][33][34][35][36][37] To anticipate the potential mechanisms of acquired resistance to metformin during the course of treatment, we recently established metformin-resistant pooled cell populations from the MCF-7 breast carcinoma cell line. Thus, to assess what impact the resistance phenomenon might have on metforminbased therapies, genome-wide analyses using Agilent 44K Whole Human Genome Arrays were evaluated using a bioinformatics approach with the ingenuity pathway analysis (IPA) software.…”

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confidence: 99%