title: Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms.
abstract: A switch from oxidative phosphorylation to glycolysis is frequently observed in cancer cells and is linked to tumor growth and invasion, but the underpinning molecular mechanisms controlling the switch are poorly understood. In this report we show that Notch signaling is a key regulator of cellular metabolism. Both hyper- and hypoactivated Notch induce a glycolytic phenotype in breast tumor cells, although by distinct mechanisms: hyperactivated Notch signaling leads to increased glycolysis through activation of the phosphatidylinositol 3-kinase/AKT serine/threonine kinase pathway, whereas hypoactivated Notch signaling attenuates mitochondrial activity and induces glycolysis in a p53-dependent manner. Despite the fact that cells with both hyper- and hypoactivated Notch signaling showed enhanced glycolysis, only cells with hyperactivated Notch promoted aggressive tumor growth in a xenograft mouse model. This phenomenon may be explained by that only Notch-hyperactivated, but not -hypoactivated, cells retained the capacity to switch back to oxidative phosphorylation. In conclusion, our data reveal a role for Notch in cellular energy homeostasis, and show that Notch signaling is required for metabolic flexibility.
authors: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20521 Turku, Finland.
authors: Sebastian K-J
authors: SK
authors: Landor
authors: Anders P
authors: AP
authors: Mutvei
authors: Veronika
authors: V
authors: Mamaeva
authors: Shaobo
authors: S
authors: Jin
authors: Morten
authors: M
authors: Busk
authors: Ronald
authors: R
authors: Borra
authors: Tove J
authors: TJ
authors: Grönroos
authors: Pauliina
authors: P
authors: Kronqvist
authors: Urban
authors: U
authors: Lendahl
authors: Cecilia Maria
authors: CM
authors: Sahlgren
mesh_terms: D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009368:Neoplasm Transplantation; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D010100:Oxygen