title: Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models.
abstract: Tumor chemoresistance is associated with high aerobic glycolysis rates and reduced oxidative phosphorylation, a phenomenon called "Warburg effect" whose reversal could impair the ability of a wide range of cancer cells to survive in the presence or absence of chemotherapy. In previous studies, Short-term-starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy but the mechanisms responsible for these effects are poorly understood. We tested the cytotoxicity of Oxaliplatin (OXP) combined with a 48hour STS on the progression of CT26 colorectal tumors. STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models. In CT26 cells, STS down-regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.
authors.affiliation: Laboratorio di Oncologia Istituto G. Gaslini, Genoa, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bianchi
authors.affiliation: Laboratorio di Oncologia Istituto G. Gaslini, Genoa, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Martella
authors.affiliation: Department of Pharmacy, University of Genoa, Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ravera
authors.affiliation: CNR Institute of Bioimages and Molecular Physiology, Milan, Section of Genoa, Genoa, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marini
authors.affiliation: Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Selene
authors.initials: S
authors.lastname: Capitanio
authors.affiliation: Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Orengo
authors.affiliation: Animal facility, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.affiliation: Core Facility, Istituto G. Gaslini, Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Lavarello
authors.affiliation: Functional Genomics, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Amaro
authors.affiliation: Core Facility, Istituto G. Gaslini, Genoa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Petretto
authors.affiliation: Functional Genomics, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
authors.affiliation: Nuclear Medicine Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Gianmario
authors.initials: G
authors.lastname: Sambuceti
authors.affiliation: Laboratorio di Oncologia Istituto G. Gaslini, Genoa, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.affiliation: Laboratorio di Oncologia Istituto G. Gaslini, Genoa, Italy.
authors.forename: Lizzia
authors.initials: L
authors.lastname: Raffaghello
authors.affiliation: Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.|Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.|IFOM, FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Valter D
authors.initials: VD
authors.lastname: Longo
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D019069:Cell Respiration / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D003110:Colonic Neoplasms / Q000378:metabolism*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005215:Fasting / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D000255:Adenosine Triphosphate
keywords: Warburg effect; colon cancer; fasting; glucose uptake; oxidative phosphorylation