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

doi:10.1016/j.molcel.2022.06.005

Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis

Mol Cell. 2022 Aug 18;82(16):3045-3060.e11. doi: 10.1016/j.molcel.2022.06.005. Epub 2022 Jun 24.

Authors

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

Affiliations

¹ Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
² Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
³ University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ Metabolomics Innovation Resource, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada.
⁵ Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA; Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁷ Division of Gastrointestinal & Endocrine Surgery, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
⁸ Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁹ Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
¹⁰ Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: chrischang@berkeley.edu.
¹¹ Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: christine.chio@columbia.edu.

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.

Keywords: PKM2; cancer metabolism; glucose oxidation; metastasis; methionine oxidation; pancreatic cancer; redox signaling.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Pancreatic Ductal* / genetics
Carrier Proteins / metabolism*
Humans
Membrane Proteins / metabolism*
Methionine
Methionine Sulfoxide Reductases / chemistry
Methionine Sulfoxide Reductases / metabolism
Oxidation-Reduction
Pancreatic Neoplasms* / genetics
Pyruvate Kinase / metabolism
Thyroid Hormone-Binding Proteins
Thyroid Hormones / metabolism*

Substances

Carrier Proteins
Membrane Proteins
Thyroid Hormones
Methionine
Methionine Sulfoxide Reductases
Pyruvate Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding