The Role of the Kynurenine/AhR Pathway in Diseases Related to Metabolism and Cancer

Abstract

The Aryl hydrocarbon receptor (AhR) is a xenobiotic and endobiotic receptor, which regulates many cellular processes from contaminant metabolism to immunomodulation. Consequently, it is also involved in pathophysiological pathways and now represents a potential therapeutical target. In this review, we will highlight the ancestral function of the protein together with an illustration of its ligand’s battery, emphasizing the different responses triggered by these high diverse molecules. Among them, several members of the kynurenine pathway (one key process of tryptophan catabolism) are AhR agonists and are subsequently involved in regulatory functions. We will finally display the interplay between Tryptophan (Trp) catabolism and dysregulation in metabolic pathways drawing hypothesis on the involvement of the AhR pathway in these cancer-related processes.

AHR signaling pathway mediates mitochondrial oxidative phosphorylation which leads to cytarabine resistance

“…It has been established that activating AHR plays a critical role in cancer cell development, invasion, and metastasis [ 4 ‒ 6 ]. Endogenous ligands of AHR include tryptophan metabolites, with the metabolism of tryptophan being mediated through two rate-limiting enzymes: TDO and IDO [ 7 , 35 ]. Recent studies suggested that interleukin-4-induced-1 (IL4I1) is more frequently associated with AHR activity than IDO1 or TDO2 [10] .…”

“…Recent studies suggested that interleukin-4-induced-1 (IL4I1) is more frequently associated with AHR activity than IDO1 or TDO2 [10] . Activating AHR enhances the expressions of cytochromes P450 (CYP1A1, 1A2, and 1B1), and increased levels of CYP1A1 and CYP1B1 indicate AHR activation [ 7 , 13 ]. The role of AHR in AML is controversial, with some studies suggesting that AHR activation promotes immune evasion by AML cells, while others suggest that it inhibits leukemic stem and progenitor cell (LSPC) proliferation in AML [ 36 , 37 ].…”

“…There is increasing evidence suggesting that AHR activation plays critical roles in tumorigenesis, including metastasis, initiation, promotion, and progression [ 4 ‒ 6 ]. Several members of the kynurenine pathway, a key process in tryptophan catabolism, are recognized as endogenous ligands for AHR [ 7 ‒ 9 ]. The conversion of Trp to N-formyl-L-kynurenine, a crucial step in the kynurenine pathway, is mediated by two rate-limiting enzymes: tryptophan 2,3-dioxygenases (TDO) and indoleamine 2,3-dioxygenases (IDO) [7] .…”

“…Several members of the kynurenine pathway, a key process in tryptophan catabolism, are recognized as endogenous ligands for AHR [ 7 ‒ 9 ]. The conversion of Trp to N-formyl-L-kynurenine, a crucial step in the kynurenine pathway, is mediated by two rate-limiting enzymes: tryptophan 2,3-dioxygenases (TDO) and indoleamine 2,3-dioxygenases (IDO) [7] . A study by Ahmed et al .…”

“…Endogenous AHR ligands are elevated in cancer patients and have been correlated with survival outcomes [ 11 ‒ 13 ]. Activation of AHR regulates the expressions of cytochromes P450 (CYP1A1, 1A2, and 1B1), and increased expression levels of these cytochromes represent AHR activation [ 7 , 13 , 14 ].…”