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Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable

Sunghee Park1, Rachid Safi1, Xiaojing Liu1

  • 1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.

Cell Reports
|June 20, 2019
PubMed

Insights

Targeting estrogen-related receptor alpha (ERRα) disrupts cancer cell metabolism by blocking pyruvate entry into mitochondria. This enhances the effectiveness of existing cancer therapies, offering new clinical strategies.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Molecular Biology

Background:

  • Cancer cells possess metabolic flexibility, adapting to nutrient and oxygen changes.
  • Targeting single metabolic pathways is challenging due to cancer cell adaptability.
  • Estrogen-related receptor alpha (ERRα) inhibition shows promise in disrupting cancer metabolism.

Purpose of the Study:

  • To elucidate the mechanism by which ERRα inhibition affects cancer cell metabolism.
  • To identify specific metabolic vulnerabilities created by ERRα inhibition.
  • To assess the potential for combination therapies involving ERRα inhibition.

Main Methods:

  • Investigated the effect of ERRα inhibition on mitochondrial pyruvate metabolism.
  • Analyzed the expression of mitochondrial pyruvate carrier 1 (MPC1) following ERRα inhibition.
  • Assessed cellular reliance on glutamine oxidation and the pentose phosphate pathway.
  • Evaluated the combined efficacy of ERRα inhibition with glutaminase and glucose-6-phosphate dehydrogenase inhibitors.

Main Results:

  • ERRα inhibition was found to impede pyruvate entry into mitochondria by downregulating MPC1 expression.
  • This metabolic shift increases cancer cell dependence on glutamine oxidation and the pentose phosphate pathway.
  • ERRα inhibition potentiates the antitumor effects of glutaminase and glucose-6-phosphate dehydrogenase inhibitors.

Conclusions:

  • ERRα inhibition creates metabolic vulnerabilities by disrupting pyruvate metabolism.
  • Combining ERRα inhibition with other metabolic inhibitors offers a promising therapeutic strategy for breast cancer.
  • Targeting ERRα represents a novel approach to overcome metabolic resistance in cancer treatment.
Keywords:
ERR⍺MPC1NADPHbreast cancerglutaminasemitochondrial metabolismnuclear receptoroxidative stresspentose phosphate pathwaypyruvate carrier

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