TY - JOUR
T1 - MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer
AU - Venkateswaran, Niranjan
AU - Lafita-Navarro, M. Carmen
AU - Hao, Yi Heng
AU - Kilgore, Jessica A.
AU - Perez-Castro, Lizbeth
AU - Braverman, Jonathan
AU - Borenstein-Auerbach, Nofit
AU - Kim, Min
AU - Lesner, Nicholas P.
AU - Mishra, Prashant
AU - Brabletz, Thomas
AU - Shay, Jerry W.
AU - DeBerardinis, Ralph J.
AU - Williams, Noelle S.
AU - Yilmaz, Omer H.
AU - Conacci-Sorrell, Maralice
N1 - Publisher Copyright:
© 2019 Venkateswaran et al.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
KW - AFMID
KW - AHR
KW - Cancer
KW - Kynurenine
KW - MYC
KW - Organoid]
KW - SLC1A5
KW - SLC7A5
KW - Tryptophan metabolism
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U2 - 10.1101/gad.327056.119
DO - 10.1101/gad.327056.119
M3 - Article
C2 - 31416966
AN - SCOPUS:85071787274
SN - 0890-9369
VL - 33
SP - 1236
EP - 1251
JO - Genes and Development
JF - Genes and Development
IS - 17-18
ER -