Novel Functions of the Transcription Factor Aryl Hydrocarbon Receptor (AHR) and Its Tryptophan-Derived Ligands in Cancer Cells

This comprehensive study delves into the metabolic reprogramming of cancer cells, focusing on the proto-oncogene MYC and the aryl hydrocarbon receptor (AHR). The role of MYC in regulating tryptophan (Trp) metabolism was investigated in colon and liver cancer cells using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our findings reveal that MYC enhances the intracellular levels of Trp and its metabolites in the kynurenine pathway, specifically increasing the expression of Trp transporters SLC7A5, SLC1A5, and the enzyme AFMID. Elevated levels of these components were observed in immortalized colon cancer cells lines and patient tissues, with a significant increase in kynurenine. Blocking enzymes in this pathway led to the preferential death of cancer cells, suggesting a potential therapeutic strategy. Furthermore, our research highlights the role of AHR in cellular detoxification and proliferation, particularly in MYC-overexpressing cells. We found that AHR knockdown reduced the expression of genes crucial for metabolic pathways necessary for cell proliferation, such as LDHA, DHODH, and UMPS. Additionally, we identified SCIN, an actin-severing protein, as a key target of AHR in colon cancer cells, necessary for cell proliferation and activation of the WNT pathway through β-catenin. In liver cancer, we discovered that MYC-driven tumors have a critical dependence on Trp, with a diminished utilization of the Trp via the Kyn pathway. Depriving these tumors of Trp inhibits their growth, while supplementation with the Trp metabolite I3P restores growth, presenting a novel therapeutic target. Overall, our findings underscore the importance of MYC and AHR in regulating amino acid metabolism in cancer and open new avenues for targeted cancer therapies.