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

Karthigayan Shanmugasundaram1, Bijaya K Nayak1, William E Friedrichs1

  • 1Department of Medicine, UT Health, San Antonio, TX, 78229, USA.

Nature Communications
|October 21, 2017
PubMed

Insights

Researchers discovered that the protein NOX4 regulates cancer drug resistance by controlling pyruvate kinase M2 (PKM2) activity. Modulating ATP levels and using cytotoxic drugs may overcome resistance in glycolytic cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • The link between glycolysis and cancer drug resistance is not fully understood.
  • NADPH oxidase (NOX) enzymes play roles in cellular signaling and disease.
  • Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme implicated in cancer.

Purpose of the Study:

  • To elucidate the molecular mechanisms connecting glycolysis to cancer drug resistance.
  • To investigate the role of NOX4 in regulating PKM2 activity and drug sensitivity.
  • To explore therapeutic strategies targeting NOX4 and ATP levels in cancer.

Main Methods:

  • Identification of an ATP-binding motif in NOX4 and assessment of ATP's regulatory effect.
  • Subcellular localization studies of NOX4 and its activation by mitochondrial ATP redistribution.
  • Analysis of NOX4-derived reactive oxygen species (ROS) on PKM2 acetylation and degradation.
  • Evaluation of NOX4 silencing effects on drug sensitivity in cancer cells and xenograft models.

Main Results:

  • ATP directly binds and negatively regulates NOX4 activity; mitochondrial ATP depletion activates NOX4.
  • NOX4-derived ROS inhibits PCAF-dependent acetylation and lysosomal degradation of PKM2.
  • NOX4 silencing sensitizes human renal carcinoma cells to drug-induced death.
  • PKM2 plays a crucial role in mediating NOX4's effect on drug resistance.

Conclusions:

  • NOX4 acts as a key regulator linking glycolysis to cancer drug resistance via PKM2.
  • Targeting NOX4 and modulating ATP levels presents a potential strategy to overcome drug resistance.
  • These findings offer novel insights into cancer evasive resistance mechanisms.

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