Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable Vulnerabilities in Breast Cancer.

Published

Journal Article

Most cancer cells exhibit metabolic flexibility, enabling them to withstand fluctuations in intratumoral concentrations of glucose (and other nutrients) and changes in oxygen availability. While these adaptive responses make it difficult to achieve clinically useful anti-tumor responses when targeting a single metabolic pathway, they can also serve as targetable metabolic vulnerabilities that can be therapeutically exploited. Previously, we demonstrated that inhibition of estrogen-related receptor alpha (ERRα) significantly disrupts mitochondrial metabolism and that this results in substantial antitumor activity in animal models of breast cancer. Here we show that ERRα inhibition interferes with pyruvate entry into mitochondria by inhibiting the expression of mitochondrial pyruvate carrier 1 (MPC1). This results in a dramatic increase in the reliance of cells on glutamine oxidation and the pentose phosphate pathway to maintain nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis. In this manner, ERRα inhibition increases the efficacy of glutaminase and glucose-6-phosphate dehydrogenase inhibitors, a finding that has clinical significance.

Full Text

Duke Authors

Cited Authors

  • Park, S; Safi, R; Liu, X; Baldi, R; Liu, W; Liu, J; Locasale, JW; Chang, C-Y; McDonnell, DP

Published Date

  • June 18, 2019

Published In

Volume / Issue

  • 27 / 12

Start / End Page

  • 3587 - 3601.e4

PubMed ID

  • 31216477

Pubmed Central ID

  • 31216477

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2019.05.066

Language

  • eng

Conference Location

  • United States