Abstract
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.
Keywords:
IDO1; IFNγ; PDAC; cancer immunology; cancer metabolism; epacadostat; formate; immunometabolism; immunotherapy; one-carbon metabolism; pancreas; serine; stellate cells; tryptophan; tumor microenvironment.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allografts
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Animals
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Antineoplastic Agents / pharmacology
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Carbon / immunology
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Carbon / metabolism
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Carcinoma, Pancreatic Ductal / drug therapy
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Carcinoma, Pancreatic Ductal / genetics*
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Carcinoma, Pancreatic Ductal / immunology
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Carcinoma, Pancreatic Ductal / mortality
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Cell Line, Tumor
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Formates / immunology
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Formates / metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics*
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Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Metabolic Networks and Pathways / drug effects
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Metabolic Networks and Pathways / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Oximes / pharmacology
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / immunology
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Pancreatic Neoplasms / mortality
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Pancreatic Stellate Cells / drug effects
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Pancreatic Stellate Cells / immunology
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Pancreatic Stellate Cells / metabolism*
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / immunology
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Serine / immunology
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Serine / metabolism
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Serine / pharmacology
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Signal Transduction
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Sulfonamides / pharmacology
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Tryptophan / immunology
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Tryptophan / metabolism
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Tryptophan / pharmacology
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Tumor Escape / drug effects*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / immunology
Substances
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Antineoplastic Agents
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Formates
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IDO1 protein, human
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IDO1 protein, mouse
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Oximes
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Sulfonamides
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Trp53 protein, mouse
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Tumor Suppressor Protein p53
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formic acid
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Serine
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epacadostat
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Carbon
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Interferon-gamma
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Tryptophan
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)