||Wednesday, 20 September 2023, 13:00～14:30
||7th Floor, Seminar Room 1, IDAC Center for Basic Aging Research
||Malignant consequences of redox signaling in pancreatic cancer
||Iok In Christine Chio, PhD
||Genetics and Development, Institute for Cancer Genetics, Columbia University Medical Center
||Hozumi Motohashi (Dept. Gene Expression Regulation・ext 8550)
||The impact of reactive oxygen species (ROS) on cancer is complex, especially given their context-dependent ability to either promote or suppress tumorigenesis. Interpreting the effects of ROS on cellular behavior is further complicated by their dual potential to indiscriminately oxidize macromolecules or to selectively oxidize redox-reactive residues of target proteins. Indeed, the thiol group of proteinaceous cysteines can serve as a reversible redox switch that regulates distinct signaling outcomes. For example, using our pancreatic organoid model, we previously showed that redox signaling through specific cysteine residues promotes protein synthesis (Cell, 2016) and tumor cell viability in pancreatic ductal adenocarcinoma (PDA) (Nat Comms, 2019). Nonetheless, it remains unclear whether redox signaling mechanisms also contribute to the high metastatic potential of PDA and, thus, the dismal prognosis associated with this malignancy. In addition to cysteine, methionine residuesharbor a redox-reactive sulfur atom that can be oxidized to methionine sulfoxide and then reduced back to methionine by methionine sulfoxide reductase A (MSRA). Based on our recent discovery that MSRA is a potent suppressor of PDA metastasis (Molecular Cell, 2022), we postulate that site-specific methionine oxidation directly regulates PDA tumorigenesis. To this end, we performed quantitative chemoproteomic analysis of the methionine proteomes of PDA cells and immune cells during disease progression and identified specific proteinaceous methionine oxidation events that support metastasis.