| Literature DB >> 35752173 |
Dan He1, Huijin Feng2, Belen Sundberg2, Jiaxing Yang2, Justin Powers2, Alec H Christian1, John E Wilkinson3, Cian Monnin4, Daina Avizonis4, Craig J Thomas5, Richard A Friedman6, Michael D Kluger7, Michael A Hollingsworth8, Paul M Grandgenett8, Kelsey A Klute9, F Dean Toste1, Christopher J Chang10, Iok In Christine Chio11.
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.Entities:
Keywords: PKM2; cancer metabolism; glucose oxidation; metastasis; methionine oxidation; pancreatic cancer; redox signaling
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Year: 2022 PMID： 35752173 PMCID： PMC9391305 DOI： 10.1016/j.molcel.2022.06.005
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 19.328