Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation

Xiao xue Li, Zhi jing Wang, Yu Zheng, Yun feng Guan, Peng bo Yang, Xiang Chen, Cong Peng, Jian ping He, Yuan li Ai, Sheng fu Wu, Kun Yi Chien, Qiao Wu*, Hang zi Chen

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

89 Scopus citations

Abstract

Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPβ, a rate-limiting enzyme in FAO. Although TPβ activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPβ association results in Nur77 self-sacrifice to protect TPβ from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPβ interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma. In this study, Li et al. demonstrate that the nuclear receptor Nur77 contributes to the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation-induced Nur77 mitochondrial translocation facilitates its interaction with TPβ, which protects TPβ from oxidation via Nur77 self-oxidation, boosting FAO to support cell survival under metabolic stress.

Original languageEnglish
Pages (from-to)480-492.e7
JournalMolecular Cell
Volume69
Issue number3
DOIs
StatePublished - 01 02 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • FAO
  • ROS
  • TPβ
  • fatty acid oxidation
  • melanoma
  • metabolic stress
  • metastasis
  • mitochondrial trifunctional protein beta subunit
  • nuclear receptor Nur77/TR3
  • protein oxidation

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