Mitochondrial glutamine metabolism via GOT2 supports pancreatic cancer growth through senescence inhibition
Autor: | Sunsook Hwang, Jeong-Hwa Lee, Sung Bin Seo, Seungyeon Yang, Seung Min Jeong, Minjoong Kim |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Senescence Cancer Research Glutamine Immunology Biology GOT2 Article 03 medical and health sciences Cellular and Molecular Neuroscience Cell Line Tumor Humans Aspartate Aminotransferases lcsh:QH573-671 Cellular Senescence Cell Proliferation Gene knockdown lcsh:Cytology Kinase HEK 293 cells Cell Biology Mitochondria Cell biology Pancreatic Neoplasms HEK293 Cells 030104 developmental biology Cell culture Cancer cell Carcinoma Pancreatic Ductal |
Zdroj: | Cell Death and Disease, Vol 9, Iss 2, Pp 1-10 (2018) Cell Death & Disease |
ISSN: | 2041-4889 |
DOI: | 10.1038/s41419-017-0089-1 |
Popis: | Cellular senescence, which leads to a cell cycle arrest of damaged or dysfunctional cells, is an important mechanism to restrain the malignant progression of cancer cells. Because metabolic changes underlie many cell-fate decisions, it has been suggested that cell metabolism might play key roles in senescence pathways. Here, we show that mitochondrial glutamine metabolism regulates senescence in human pancreatic ductal adenocarcinoma (PDAC) cells. Glutamine deprivation or inhibition of mitochondrial aspartate transaminase (GOT2) results in a profound induction of senescence and a suppression of PDAC growth. Glutamine carbon flow through GOT2 is required to create NADPH and to maintain the cellular redox state. We found that elevated reactive oxygen species levels by GOT2 knockdown lead to the cyclin-dependent kinase inhibitor p27-mediated senescence. Importantly, PDAC cells exhibit distinct dependence on this pathway, whereas knockdown of GOT2 did not induce senescence in non-transformed cells. The essentiality of GOT2 in senescence regulation of PDAC, which is dispensable in their normal counterparts, may have profound implications for the development of strategies to treat these refractory cancers. |
Databáze: | OpenAIRE |
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