NOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to drug resistance

Nat Commun. 2017 Oct 19;8(1):997. doi: 10.1038/s41467-017-01106-1.

Abstract

The molecular mechanisms that couple glycolysis to cancer drug resistance remain unclear. Here we identify an ATP-binding motif within the NADPH oxidase isoform, NOX4, and show that ATP directly binds and negatively regulates NOX4 activity. We find that NOX4 localizes to the inner mitochondria membrane and that subcellular redistribution of ATP levels from the mitochondria act as an allosteric switch to activate NOX4. We provide evidence that NOX4-derived reactive oxygen species (ROS) inhibits P300/CBP-associated factor (PCAF)-dependent acetylation and lysosomal degradation of the pyruvate kinase-M2 isoform (PKM2). Finally, we show that NOX4 silencing, through PKM2, sensitizes cultured and ex vivo freshly isolated human-renal carcinoma cells to drug-induced cell death in xenograft models and ex vivo cultures. These findings highlight yet unidentified insights into the molecular events driving cancer evasive resistance and suggest modulation of ATP levels together with cytotoxic drugs could overcome drug-resistance in glycolytic cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis / drug effects*
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Drug Resistance, Neoplasm*
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology*
  • Etoposide / pharmacology
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • NADPH Oxidase 4 / metabolism*
  • Reactive Oxygen Species / metabolism
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / metabolism
  • Xenograft Model Antitumor Assays
  • p300-CBP Transcription Factors / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • Carrier Proteins
  • Membrane Proteins
  • Reactive Oxygen Species
  • Thyroid Hormones
  • Etoposide
  • NADPH Oxidase 4
  • NOX4 protein, human
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor