title: Oncogene-mediated tumor transformation sensitizes cells to autophagy induction.
abstract: The process of tumorigenesis induces alterations in numerous cellular pathways including the main eukaryotic metabolic routes. It has been recently demonstrated that autophagy is part of the oncogene-induced senescence phenotype although its role in tumor establishment has not been completely clarified. In the present study, we showed that non‑transformed cells are sensitized to mitochondrial stress and autophagy induction when they are transformed by oncogenes such as c-Myc or Ras. We observed that overexpression of c-Myc or Ras increased AMP-activated protein kinase (AMPK) phosphorylation and the expression of p62, a known partner for degradation by autophagy. The activation of AMPK was found to favor the activation of FoxO3 which was prevented by the inhibition of AMPK. The transcriptional activation mediated by FoxO3 upregulated genes such as BNIP3 and LC3. Finally, the transformation by oncogenes such as c-Myc and Ras predisposes tumor cells to autophagy induction as a consequence of mitochondrial stress and impairs tumor growth in vitro and in vivo, which may have therapeutic implications.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autonoma de Madrid, 28049 Madrid, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gargini
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autonoma de Madrid, 28049 Madrid, Spain.
authors.forename: Vega
authors.initials: V
authors.lastname: García-Escudero
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autonoma de Madrid, 28049 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Izquierdo
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autonoma de Madrid, 28049 Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Wandosell
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D008928:Mitochondria / Q000473:pathology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C090121:BNIP3 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C477012:MAP1LC3A protein, human; C489427:MYC protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C118585:P62 protein, human; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D055372:AMP-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)