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

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 journal › Article › peer-review

45 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 language	English (US)
Pages (from-to)	3045-3060.e11
Journal	Molecular Cell
Volume	82
Issue number	16
DOIs	https://doi.org/10.1016/j.molcel.2022.06.005
State	Published - 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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10.1016/j.molcel.2022.06.005

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He, D., Feng, H., Sundberg, B., Yang, J., Powers, J., Christian, A. H., Wilkinson, J. E., Monnin, C., Avizonis, D., Thomas, C. J., Friedman, R. A., Kluger, M. D., Hollingsworth, M. A., Grandgenett, P. M., Klute, K. A., Toste, F. D., Chang, C. J., & Chio, I. I. C. (2022). Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis. Molecular Cell, 82(16), 3045-3060.e11. https://doi.org/10.1016/j.molcel.2022.06.005

He, D, Feng, H, Sundberg, B, Yang, J, Powers, J, Christian, AH, Wilkinson, JE, Monnin, C, Avizonis, D, Thomas, CJ, Friedman, RA, Kluger, MD, Hollingsworth, MA, Grandgenett, PM, Klute, KA, Toste, FD, Chang, CJ & Chio, IIC 2022, 'Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis', Molecular Cell, vol. 82, no. 16, pp. 3045-3060.e11. https://doi.org/10.1016/j.molcel.2022.06.005

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title = "Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis",

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",

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

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doi = "10.1016/j.molcel.2022.06.005",

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AU - He, Dan

AU - Feng, Huijin

AU - Sundberg, Belen

AU - Yang, Jiaxing

AU - Powers, Justin

AU - Christian, Alec H.

AU - Wilkinson, John E.

AU - Monnin, Cian

AU - Avizonis, Daina

AU - Thomas, Craig J.

AU - Friedman, Richard A.

AU - Kluger, Michael D.

AU - Hollingsworth, Michael A.

AU - Grandgenett, Paul M.

AU - Klute, Kelsey A.

AU - Toste, F. Dean

AU - Chang, Christopher J.

AU - Chio, Iok In Christine

PY - 2022/8/18

Y1 - 2022/8/18

N2 - 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.

AB - 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.

KW - PKM2

KW - cancer metabolism

KW - glucose oxidation

KW - metastasis

KW - methionine oxidation

KW - pancreatic cancer

KW - redox signaling

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Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis

Abstract

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