Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models

// Giovanna Bianchi 1,* , Roberto Martella 1,* , Silvia Ravera 2 , Cecilia Marini 3 , Selene Capitanio 4 , Annamaria Orengo 4 , Laura Emionite 5 , Chiara Lavarello 6 , Adriana Amaro 7 , Andrea Petretto 6 , Ulrich Pfeffer 7 , Gianmario Sambuceti 4 , Vito Pistoia 1 , Lizzia Raffaghello 1,** and Valter D. Longo 8,9,10,** 1 Laboratorio di Oncologia Istituto G. Gaslini, Genoa, Italy 2 Department of Pharmacy, University of Genoa, Genova, Italy 3 CNR Institute of Bioimages and Molecular Physiology, Milan, Section of Genoa, Genoa, Italy 4 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 5 Animal facility, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 6 Core Facility, Istituto G. Gaslini, Genoa, Italy 7 Functional Genomics, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 8 Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA 9 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 10 IFOM, FIRC Institute of Molecular Oncology, Milan, Italy * These authors have contributed equally as first authors ** These authors have contributed equally as last authors Correspondence to: Valter D. Longo, email: // Keywords : fasting, Warburg effect, colon cancer, oxidative phosphorylation, glucose uptake Received : March 04, 2015 Accepted : March 11, 2015 Published : March 30, 2015 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.