Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells
| Autor: | Dimitris Athineos, Oliver D. K. Maddocks, Tong Zhang, Karen Blyth, Alice C Newman, Mattia Falcone, Matthias Pietzke, Alexei Vazquez, Alejandro Huerta Uribe |
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| Rok vydání: | 2020 |
| Předmět: |
Formates
immunometabolism cancer metabolism Serine Mice 0302 clinical medicine IDO1 Oximes Nucleotide pancreas Cancer immunology chemistry.chemical_classification 0303 health sciences Sulfonamides Pancreatic Stellate Cells Allografts epacadostat Cell biology Gene Expression Regulation Neoplastic immunotherapy Metabolic Networks and Pathways Carcinoma Pancreatic Ductal Signal Transduction stellate cells Mice Nude Antineoplastic Agents Biology cancer immunology Article Proto-Oncogene Proteins p21(ras) serine 03 medical and health sciences Interferon-gamma Immune system formate Pancreatic cancer Cell Line Tumor medicine Animals Humans Indoleamine-Pyrrole 2 3 -Dioxygenase tumor microenvironment tryptophan Molecular Biology 030304 developmental biology Tumor microenvironment PDAC Cell Biology medicine.disease one-carbon metabolism Carbon Mice Inbred C57BL Pancreatic Neoplasms chemistry Cancer cell Hepatic stellate cell Tumor Escape Tumor Suppressor Protein p53 030217 neurology & neurosurgery IFNγ |
| Zdroj: | Molecular Cell |
| ISSN: | 1097-4164 |
| Popis: | Summary Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis. Graphical abstract Highlights • IFNγ and attachment-independent growth promote IDO1 expression in PDAC cells • Metabolism of tryptophan by IDO1 contributes one-carbons to the THF cycle • Tryptophan can substitute for serine as a one-carbon source • Serine and glycine restriction enhances the anti-tumor activity of an IDO1 inhibitor Newman et al. studied the metabolic outcomes of immune-regulated IDO1 expression in pancreatic cancer and stellate cells, reporting that IDO1-dependent tryptophan metabolism is a bona fide one-carbon source for folate-dependent nucleotide synthesis. Tryptophan substituted for serine as a one-carbon donor, with serine restriction improving the anti-tumor activity of IDO1 inhibitor epacadostat. |
| Databáze: | OpenAIRE |
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