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The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling

Lucas B Sullivan1, Eva Martinez-Garcia, Hien Nguyen

  • 1Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Molecular Cell
|June 11, 2013
PubMed

Insights

Fumarate hydratase (FH) loss in cancer cells increases fumarate, which depletes glutathione. This leads to reactive oxygen species (ROS) accumulation and activates HIF-1, promoting tumor growth.

Area of Science:

  • Biochemistry
  • Oncology
  • Cell Biology

Background:

  • Fumarate hydratase (FH) is a tumor suppressor in renal cell carcinoma.
  • FH-deficient cancer cells exhibit elevated fumarate, reactive oxygen species (ROS), and HIF-1 activation.
  • Mechanisms linking FH loss to increased ROS and HIF-1 are unclear.

Purpose of the Study:

  • Investigate how FH loss leads to increased fumarate, ROS, and HIF-1 activation.
  • Elucidate the role of glutamine metabolism in this process.
  • Identify fumarate's molecular targets and downstream effects.

Main Methods:

  • Utilized human FH-deficient cancer cells.
  • Analyzed glutamine-dependent oxidative citric acid cycle metabolism.
  • Performed in vitro and in vivo experiments to study fumarate-glutathione interactions.
  • Assessed NADPH levels, mitochondrial ROS, and histone methylation.

Main Results:

  • Glutamine metabolism fuels fumarate production, increasing ROS and HIF-1.
  • Accumulated fumarate binds glutathione, forming succinated glutathione (GSF).
  • GSF impairs glutathione reductase, reducing NADPH and boosting mitochondrial ROS.
  • Elevated ROS correlates with histone hypermethylation.

Conclusions:

  • Fumarate acts as a proto-oncometabolite by depleting glutathione.
  • This mechanism drives ROS accumulation and HIF-1 activation in FH-deficient cancers.
  • FH loss promotes a pro-tumorigenic environment through metabolic alterations.

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