mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells

Cancer Cell. 2016 Apr 11;29(4):548-562. doi: 10.1016/j.ccell.2016.02.018. Epub 2016 Mar 24.

Abstract

Although glycolysis is substantially elevated in many tumors, therapeutic targeting of glycolysis in cancer patients has not yet been successful, potentially reflecting the metabolic plasticity of tumor cells. In various cancer cells exposed to a continuous glycolytic block, we identified a recurrent reprogramming mechanism involving sustained mTORC1 signaling that underlies escape from glycolytic addiction. Active mTORC1 directs increased glucose flux via the pentose phosphate pathway back into glycolysis, thereby circumventing a glycolysis block and ensuring adequate ATP and biomass production. Combined inhibition of glycolysis and mTORC1 signaling disrupted metabolic reprogramming in tumor cells and inhibited their growth in vitro and in vivo. These findings reveal novel combinatorial therapeutic strategies to realize the potential benefit from targeting the Warburg effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Carcinoma / pathology
  • Cell Line, Tumor
  • Citric Acid Cycle
  • Combined Modality Therapy
  • Cytokines / antagonists & inhibitors
  • Cytokines / genetics
  • Deoxyglucose / pharmacology
  • Deoxyglucose / therapeutic use
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Energy Metabolism / drug effects
  • Everolimus / pharmacology
  • Everolimus / therapeutic use
  • Female
  • Glucose-6-Phosphate Isomerase / antagonists & inhibitors
  • Glucose-6-Phosphate Isomerase / genetics
  • Glutaminase / antagonists & inhibitors
  • Glutaminase / physiology
  • Glutamine / metabolism
  • Glycolysis* / drug effects
  • Hep G2 Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Metabolomics
  • Mice
  • Mice, Nude
  • Molecular Targeted Therapy*
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / physiology*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology*
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Pentose Phosphate Pathway / drug effects
  • Pentose Phosphate Pathway / physiology
  • RNA Interference
  • RNA, Small Interfering / therapeutic use
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa / physiology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / physiology*
  • Tumor Stem Cell Assay
  • Xenograft Model Antitumor Assays

Substances

  • Cytokines
  • Multiprotein Complexes
  • Neoplasm Proteins
  • RNA, Small Interfering
  • Glutamine
  • Adenosine Triphosphate
  • Deoxyglucose
  • Everolimus
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Glutaminase
  • GPI protein, human
  • Glucose-6-Phosphate Isomerase