title: Activation of AMP-activated protein kinase (AMPK) provides a metabolic barrier to reprogramming somatic cells into stem cells.
abstract: The ability of somatic cells to reprogram their ATP-generating machinery into a Warburg-like glycolytic metabotype while overexpressing stemness genes facilitates their conversion into either induced pluripotent stem cells (iPSCs) or tumor-propagating cells. AMP-activated protein kinase (AMPK) is a metabolic master switch that senses and decodes intracellular changes in energy status; thus, we have evaluated the impact of AMPK activation in regulating the generation of iPSCs from nonstem cells of somatic origin. The indirect and direct activation of AMPK with the antidiabetic biguanide metformin and the thienopyridone A-769662, respectively, impeded the reprogramming of mouse embryonic and human diploid fibroblasts into iPSCs. The AMPK activators established a metabolic barrier to reprogramming that could not be bypassed, even through p53 deficiency, a fundamental mechanism to greatly improve the efficiency of stem-cell production. Treatment with metformin or A-769662 before the generation of iPSC colonies was sufficient to drastically decrease iPSC generation, suggesting that AMPK activation impedes early stem cell genetic reprogramming. Monitoring the transcriptional activation status of each individual reprogramming factor (i.e., Oct4, Sox2, Klf4 and c-Myc) revealed that AMPK activation notably prevented the transcriptional activation of Oct4, the master regulator of the pluripotent state. AMPK activation appears to impose a normalized metabolic flow away from the required pro-immortalizing glycolysis that fuels the induction of stemness and pluripotency, endowing somatic cells with an energetic infrastructure that is protected against reprogramming. AMPK-activating anti-reprogramming strategies may provide a roadmap for the generation of novel cancer therapies that metabolically target tumor-propagating cells.
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology (ICO), Girona, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vazquez-Martin
authors.forename: Luciano
authors.initials: L
authors.lastname: Vellon
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Quirós
authors.forename: Sílvia
authors.initials: S
authors.lastname: Cufí
authors.forename: Eunate
authors.initials: E
authors.lastname: Ruiz de Galarreta
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliveras-Ferraros
authors.forename: Angel G
authors.initials: AG
authors.lastname: Martin
authors.forename: Begoña
authors.initials: B
authors.lastname: Martin-Castillo
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001713:Biphenyl Compounds; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; D016271:Proto-Oncogene Proteins c-myc; D011753:Pyrones; D055748:SOXB1 Transcription Factors; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile