Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis

• DOI: 10.1016/j.molcel.2022.06.005
• Publication Date: 2022-06-24T14:58:42Z
• Authors: 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. Hollin...; Paul M. Grandgenett; Kelsey A. Klute; F. Dean Toste; Christopher J. Chang; Iok In Christine ...
• Keywords: 0301 basic medicine; Thyroid Hormones; Biomedical and clinical sciences; Oncology and Carcinogenesis; pancreatic cancer; Pyruvate Kinase; 610; cancer metabolism; Medical and Health Sciences; methionine oxidation; Pancreatic Cancer; 03 medical and health sciences; Rare Diseases; Methionine; 2.1 Biological and endogenous factors; metastasis; Humans; redox signaling; Cancer; Biomedical and Clinical Sciences; Carcinoma; Health sciences; Membrane Proteins; glucose oxidation; Biological Sciences; 3. Good health; Pancreatic Neoplasms; Biological sciences; Pancreatic Ductal; Methionine Sulfoxide Reductases; Biochemistry and Cell Biology; Digestive Diseases; Carrier Proteins; Oxidation-Reduction; PKM2; Developmental Biology; Carcinoma, Pancreatic Ductal; Thyroid Hormone-Binding Proteins

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.