1. Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis.
- Author
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Venkateswaran N, Garcia R, Lafita-Navarro MC, Hao YH, Perez-Castro L, Nogueira PAS, Solmonson A, Mender I, Kilgore JA, Fang S, Brown IN, Li L, Parks E, Lopes Dos Santos I, Bhaskar M, Kim J, Jia Y, Lemoff A, Grishin NV, Kinch L, Xu L, Williams NS, Shay JW, DeBerardinis RJ, Zhu H, and Conacci-Sorrell M
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Kynurenine metabolism, Mice, Inbred C57BL, Liver metabolism, Liver pathology, Male, Tryptophan metabolism, Liver Neoplasms metabolism, Liver Neoplasms genetics, Liver Neoplasms pathology, Indoles metabolism, Indoles pharmacology, Proto-Oncogene Proteins c-myc metabolism, Proto-Oncogene Proteins c-myc genetics, Carcinogenesis metabolism, Carcinogenesis genetics
- Abstract
Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. Thus, characterization of nutrient demands by individual tumor types may identify specific vulnerabilities that can be manipulated to target the destruction of cancer cells. We find that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. We define a crucial role for the Trp-derived metabolite indole 3-pyruvate (I3P) in liver tumor growth. I3P supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment., (© 2024. The Author(s).)
- Published
- 2024
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