1. Nutritional Stress Induced by Tryptophan-Degrading Enzymes Results in ATF4-Dependent Reprogramming of the Amino Acid Transporter Profile in Tumor Cells.
- Author
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Timosenko E, Ghadbane H, Silk JD, Shepherd D, Gileadi U, Howson LJ, Laynes R, Zhao Q, Strausberg RL, Olsen LR, Taylor S, Buffa FM, Boyd R, and Cerundolo V
- Subjects
- Cell Line, Tumor, Humans, Activating Transcription Factor 4 physiology, Amino Acid Transport System ASC physiology, Amino Acid Transport Systems genetics, Cellular Reprogramming, Indoleamine-Pyrrole 2,3,-Dioxygenase physiology, Minor Histocompatibility Antigens physiology, Neoplasms metabolism, Tryptophan metabolism
- Abstract
Tryptophan degradation is an immune escape strategy shared by many tumors. However, cancer cells' compensatory mechanisms remain unclear. We demonstrate here that a shortage of tryptophan caused by expression of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) resulted in ATF4-dependent upregulation of several amino acid transporters, including SLC1A5 and its truncated isoforms, which in turn enhanced tryptophan and glutamine uptake. Importantly, SLC1A5 failed to be upregulated in resting human T cells kept under low tryptophan conditions but was enhanced upon cognate antigen T-cell receptor engagement. Our results highlight key differences in the ability of tumor and T cells to adapt to tryptophan starvation and provide important insights into the poor prognosis of tumors coexpressing IDO and SLC1A5. Cancer Res; 76(21); 6193-204. ©2016 AACR., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)
- Published
- 2016
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