Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis,Molecular Cell

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Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis
Molecular Cell ( IF 16.0 ) Pub Date : 2022-06-24 , DOI: 10.1016/j.molcel.2022.06.005
Dan He ₁ , Huijin Feng ₂ , Belen Sundberg ₂ , Jiaxing Yang ₂ , Justin Powers ₂ , Alec H Christian ₁ , John E Wilkinson ₃ , Cian Monnin ₄ , Daina Avizonis ₄ , Craig J Thomas ₅ , Richard A Friedman ₆ , Michael D Kluger ₇ , Michael A Hollingsworth ₈ , Paul M Grandgenett ₈ , Kelsey A Klute ₉ , F Dean Toste ₁ , Christopher J Chang ₁₀ , Iok In Christine Chio ₂

Affiliation

Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
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.
University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Metabolomics Innovation Resource, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada.
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.
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.
Division of Gastrointestinal & Endocrine Surgery, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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.

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.

中文翻译：

蛋氨酸氧化激活丙酮酸激酶M2促进胰腺癌转移

癌症死亡率主要是其转移扩散的结果。在此，我们报道甲硫氨酸亚砜还原酶 A (MSRA) 可以还原氧化的甲硫氨酸残基，可作为胰腺导管腺癌 (PDA) 转移的抑制剂。PDA 患者的转移性肿瘤中 MSRA 表达降低，而原代 PDA 细胞中 MSRA 的缺失会促进迁移和侵袭。胰腺类器官的化学蛋白质组学分析表明，MSRA 缺失会导致丙酮酸激酶 M2 (PKM2) 中的蛋氨酸残基 (M239) 选择性氧化。此外，M239氧化使PKM2维持在活性四聚体状态，以促进呼吸、迁移和转移，而PKM2的药理学激活则增加体内细胞迁移和转移。这些结果表明，蛋氨酸残基可以充当可逆的氧化还原开关，控制不同的信号转导结果，并且 MSRA-PKM2 轴充当氧化还原生物学和癌症代谢之间的调节纽带，以控制肿瘤转移。

更新日期：2022-06-24

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