MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer
- Niranjan Venkateswaran1,
- M. Carmen Lafita-Navarro1,
- Yi-Heng Hao1,
- Jessica A. Kilgore2,
- Lizbeth Perez-Castro1,
- Jonathan Braverman3,
- Nofit Borenstein-Auerbach1,
- Min Kim4,
- Nicholas P. Lesner5,
- Prashant Mishra5,6,
- Thomas Brabletz7,
- Jerry W. Shay1,8,
- Ralph J. DeBerardinis5,9,
- Noelle S. Williams2,
- Omer H. Yilmaz3,10 and
- Maralice Conacci-Sorrell1,8
- 1Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 3Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 4Lydia Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 5Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 6Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 7Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nurnberg, Erlangen 91054, Germany;
- 8Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 9Howard Hughes Medical Institute, Dallas, Texas 75390, USA;
- 10Department of Pathology, Massachusetts General Hospital Boston, Harvard Medical School, Boston, Massachusetts 02114, USA
- Corresponding author: maralice.conaccisorrell{at}utsouthwestern.edu
Abstract
Tumors display increased uptake and processing of nutrients to fulfill the demands of rapidly proliferating cancer cells. Seminal studies have shown that the proto-oncogene MYC promotes metabolic reprogramming by altering glutamine uptake and metabolism in cancer cells. How MYC regulates the metabolism of other amino acids in cancer is not fully understood. Using high-performance liquid chromatography (HPLC)-tandem mass spectrometry (LC-MS/MS), we found that MYC increased intracellular levels of tryptophan and tryptophan metabolites in the kynurenine pathway. MYC induced the expression of the tryptophan transporters SLC7A5 and SLC1A5 and the enzyme arylformamidase (AFMID), involved in the conversion of tryptophan into kynurenine. SLC7A5, SLC1A5, and AFMID were elevated in colon cancer cells and tissues, and kynurenine was significantly greater in tumor samples than in the respective adjacent normal tissue from patients with colon cancer. Compared with normal human colonic epithelial cells, colon cancer cells were more sensitive to the depletion of tryptophan. Blocking enzymes in the kynurenine pathway caused preferential death of established colon cancer cells and transformed colonic organoids. We found that only kynurenine and no other tryptophan metabolite promotes the nuclear translocation of the transcription factor aryl hydrocarbon receptor (AHR). Blocking the interaction between AHR and kynurenine with CH223191 reduced the proliferation of colon cancer cells. Therefore, we propose that limiting cellular kynurenine or its downstream targets could present a new strategy to reduce the proliferation of MYC-dependent cancer cells.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.327056.119.
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Freely available online through the Genes & Development Open Access option.
- Received April 1, 2019.
- Accepted July 12, 2019.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
