Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis

Dan He, Huijin Feng, Belen Sundberg, Jiaxing Yang, Justin Powers, Alec H. Christian, John E. Wilkinson, Cian Monnin, Daina Avizonis, Craig J. Thomas, Richard A. Friedman, Michael D. Kluger, Michael A. Hollingsworth, Paul M. Grandgenett, Kelsey A. Klute, F. Dean Toste, Christopher J. Chang, Iok In Christine Chio

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Cancer mortality is primarily a consequence of its metastatic spread. Here, we report that methionine sulfoxide reductase A (MSRA), which can reduce oxidized methionine residues, acts as a suppressor of pancreatic ductal adenocarcinoma (PDA) metastasis. MSRA expression is decreased in the metastatic tumors of PDA patients, whereas MSRA loss in primary PDA cells promotes migration and invasion. Chemoproteomic profiling of pancreatic organoids revealed that MSRA loss results in the selective oxidation of a methionine residue (M239) in pyruvate kinase M2 (PKM2). Moreover, M239 oxidation sustains PKM2 in an active tetrameric state to promote respiration, migration, and metastasis, whereas pharmacological activation of PKM2 increases cell migration and metastasis in vivo. These results demonstrate that methionine residues can act as reversible redox switches governing distinct signaling outcomes and that the MSRA-PKM2 axis serves as a regulatory nexus between redox biology and cancer metabolism to control tumor metastasis.

Original languageEnglish (US)
Pages (from-to)3045-3060.e11
JournalMolecular Cell
Volume82
Issue number16
DOIs
StatePublished - Aug 18 2022

Keywords

  • PKM2
  • cancer metabolism
  • glucose oxidation
  • metastasis
  • methionine oxidation
  • pancreatic cancer
  • redox signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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