Abstract
Tryptophan is one of the eight essential amino acids that must be obtained from the diet. Interestingly, tryptophan is the least abundant amino acid in most proteins, a large portion of cellular tryptophan is converted into metabolites of the serotonin and kynurenine pathways. In a recent study, (Venkateswaran, Lafita-Navarro et al., 2019, Genes Dev), we discovered that colon cancer cells display greater uptake and processing of tryptophan than normal colonic cells and tissues. This process is mediated by the oncogenic transcription factor MYC that promotes the expression of the tryptophan importers SLC1A5 and SLC7A5 and the tryptophan metabolizing enzyme AFMID. The metabolism of tryptophan in colon cancer cells generates kynurenine, a biologically active metabolite necessary to maintain continuous cell proliferation. Our results indicate that kynurenine functions as an oncometabolite, at least in part, by activating the transcription factor AHR, which then regulates growth promoting genes in cancer cells. We propose that blocking kynurenine production or activity can be an efficient approach to specifically limit the growth of colon cancer cells. Here, we describe our findings and new questions for future studies targeted at understanding AHR-independent function of kynurenine, as well as interfering with the enzyme AFMID as a new strategy to target the kynurenine pathway.
Highlights
TRYPTOPHAN IS PREFERENTIALLY CONVERTED INTO KYNURENINE IN COLON CANCER Tryptophan can be utilized in three ways intracellularly: it can be incorporated into newly synthesized proteins, it can be processed by the serotonin pathway to give rise to serotonin and melatonin, and it can be processed by the kynurenine pathway to generate multiple biologically active catabolites (Figure 1)
Kynurenine can be converted into kynurenic acid through the activity of kynurenine aminotransferase (KAT), into 3-hydroxy kynurenine by kynurenine 3-monooxygenase (KMO) or into anthranilic acid by kynureninase (KYNU). 3-hydroxy kynurenine is further metabolized into cinnabarinic acid, picolinic acid, or quinolinic acid, which gives rise to nicotinamide adenine dinucleotide (NAD), a co-enzyme that mediates redox reactions in a number of metabolic pathways, including glycolysis
Enzymes involved in further degrading kynurenine into downstream catabolites are not upregulated in the colon cancer samples, suggesting that kynurenine is a predominant metabolite of this pathway in colon cancer cells
Summary
TRYPTOPHAN IS PREFERENTIALLY CONVERTED INTO KYNURENINE IN COLON CANCER Tryptophan can be utilized in three ways intracellularly: it can be incorporated into newly synthesized proteins, it can be processed by the serotonin pathway to give rise to serotonin and melatonin, and it can be processed by the kynurenine pathway to generate multiple biologically active catabolites (Figure 1). * Corresponding Author: Maralice Conacci-Sorrell, UT Southwestern Medical Center, Department of Cell Biology 6000 Harry Hines Blvd., NL5.140A Dallas, TX 75390-9093; E-mail: maralice.conaccisorrell@utsouthwestern.edu In a recent study, (Venkateswaran, Lafita-Navarro et al, 2019, Genes Dev), we discovered that colon cancer cells display greater uptake and processing of tryptophan than normal colonic cells and tissues.
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