Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide. Academic Article uri icon

Overview

MeSH

  • Animals
  • Apoptosis Regulatory Proteins
  • Autophagy-Related Protein 5
  • Beclin-1
  • Caspase 1
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cellular Reprogramming
  • Chloroquine
  • Enzyme Inhibitors
  • Glucose
  • Hydroxychloroquine
  • Lysosomal-Associated Membrane Protein 2
  • Mice
  • Mice, Inbred A
  • Mice, Transgenic
  • Microtubule-Associated Proteins
  • Mitochondria
  • NF-kappa B
  • Oxygen Consumption
  • RNA Interference
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Signal Transduction
  • Teratogens

MeSH Major

  • 6-Aminonicotinamide
  • Autophagy
  • Multiprotein Complexes
  • Pentose Phosphate Pathway
  • TOR Serine-Threonine Kinases
  • Tumor Suppressor Proteins

abstract

  • The mammalian target of rapamycin complex 1 (mTORC1) is hyperactive in many human cancers and in tuberous sclerosis complex (TSC). Autophagy, a key mTORC1-targeted process, is a critical determinant of metabolic homeostasis. Metabolomic profiling was performed to elucidate the cellular consequences of autophagy dysregulation under conditions of hyperactive mTORC1. It was discovered that TSC2-null cells have distinctive autophagy-dependent pentose phosphate pathway (PPP) alterations. This was accompanied by enhanced glucose uptake and utilization, decreased mitochondrial oxygen consumption, and increased mitochondrial reactive oxygen species (ROS) production. Importantly, these findings revealed that the PPP is a key autophagy-dependent compensatory metabolic mechanism. Furthermore, PPP inhibition with 6-aminonicotinamide (6-AN) in combination with autophagy inhibition suppressed proliferation and prompted the activation of NF-κB and CASP1 in TSC2-deficient, but not TSC2-proficient cells. These data demonstrate that TSC2-deficient cells can be therapeutically targeted, without mTORC1 inhibitors, by focusing on their metabolic vulnerabilities. This study provides proof-of-concept that therapeutic targeting of diseases with hyperactive mTORC1 can be achieved without the application of mTORC1 inhibitors. ©2013 AACR.

publication date

  • January 2014

has subject area

  • 6-Aminonicotinamide
  • Animals
  • Apoptosis Regulatory Proteins
  • Autophagy
  • Autophagy-Related Protein 5
  • Beclin-1
  • Caspase 1
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cellular Reprogramming
  • Chloroquine
  • Enzyme Inhibitors
  • Glucose
  • Hydroxychloroquine
  • Lysosomal-Associated Membrane Protein 2
  • Mice
  • Mice, Inbred A
  • Mice, Transgenic
  • Microtubule-Associated Proteins
  • Mitochondria
  • Multiprotein Complexes
  • NF-kappa B
  • Oxygen Consumption
  • Pentose Phosphate Pathway
  • RNA Interference
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Teratogens
  • Tumor Suppressor Proteins

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4030750

Digital Object Identifier (DOI)

  • 10.1158/1541-7786.MCR-13-0258-T

PubMed ID

  • 24296756

Additional Document Info

start page

  • 48

end page

  • 57

volume

  • 12

number

  • 1