The complex biology of aryl hydrocarbon receptor activation in cancer and beyond

Opitz, Christiane A.; Holfelder, Pauline; Prentzell, Mirja Tamara; Trump, Saskia

doi:10.1016/j.bcp.2023.115798

Cited by 16 publications

(9 citation statements)

References 268 publications

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“…At the same time, however, MTORC1 remains active and selectively phosphorylates EIF4EBP1, which expands the common view that amino acid limitation inhibits MTORC1 79,80 . EIF4EBP1-sensitive translation promotes expression of the AHR, known to be activated by Trp via its catabolites [62][63][64][65] . However, we find that also Trp stress activates the AHR.…”

Section: Discussionmentioning

confidence: 99%

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The MTORC1-AHR pathway sustains translation and autophagy in tumours under tryptophan stress

Pfänder

Hensen

Navas

et al. 2023

Preprint

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Limited supply and catabolism restrict the essential amino acid tryptophan (Trp) in tumors. How tumors sustain translation under Trp stress remains unclear. Unlike other amino acids, Trp stress activates the EGFR, which enhances macropinocytosis and RAS signaling to the MTORC1 and p38/MAPK kinases, sustaining translation. The AHR forms part of the Trp stress proteome and promotes autophagy to sustain Trp levels, and ceramide biosynthesis. Thus, Trp restriction elicits pro-translation signals enabling adaptation to nutrient stress, placing Trp into a unique position in the amino acid-mediated stress response. Our findings challenge the current perception that Trp restriction inhibits MTORC1 and the AHR and explain how both cancer drivers remain active. A glioblastoma patient subgroup with enhanced MTORC1 and AHR displays an autophagy signature, highlighting the clinical relevance of MTORC1-AHR crosstalk. Regions of high Trp or high ceramides are mutually exclusive, supporting that low Trp activates the EGFR-MTORC1-AHR axis in glioblastoma tissue.

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Section: Discussionmentioning

confidence: 99%

“…3w-y). This finding was unexpected as the AHR is typically considered to be activated by Trp metabolites [62][63][64][65] , but not under Trp restriction when Trp metabolites are low or absent.…”

Section: Eif4ebp1-sensitive Translation Induces Ahr Expression and Ac...mentioning

confidence: 99%

The MTORC1-AHR pathway sustains translation and autophagy in tumours under tryptophan stress

Pfänder

Hensen

Navas

et al. 2023

Preprint

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“…These receptors are the aryl hyrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPAR α ) [ 16 , 17 ]. Regulation of XMEs is a relatively short-term molecular response to the exposure to chemicals; it is possible that longer term adaptation mechanisms involving epigenetic regulation also contribute [ 18 ], but these have been less studied until now and they will be discussed below in a dedicated chapter.…”

Section: The Biological Adaptation To Exogenous Chemicalsmentioning

confidence: 99%

“…Studies on the epigenetic regulation of the AhR pathway have shown that the AhR gene as well as the AhR-target genes are regulated by epigenetic modifications, including DNA methylation, histone modification and miRNA [ 18 ]. These regulations were shown to be relevant for cell-type specific expression and in different disease states such as cancer [ 61 , 62 ].…”

Section: Long-term Adaptation and Epigeneticsmentioning

confidence: 99%

Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways

Tomkiewicz,

Coumoul,

Nioche

et al. 2024

Phil. Trans. R. Soc. B

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Organisms adapt to their environment through different pathways. In vertebrates, xenobiotics are detected, metabolized and eliminated through the inducible xenobiotic-metabolizing pathways (XMP) which can also generate reactive toxic intermediates. In this review, we will discuss the impacts of the chemical exposome complexity on the balance between detoxication and side effects. There is a large discrepancy between the limited number of proteins involved in these pathways (few dozens) and the diversity and complexity of the chemical exposome (tens of thousands of chemicals). Several XMP proteins have a low specificity which allows them to bind and/or metabolize a large number of chemicals. This leads to undesired consequences, such as cross-inhibition, inefficient metabolism, release of toxic intermediates, etc. Furthermore, several XMP proteins have endogenous functions that may be disrupted upon exposure to exogenous chemicals. The gut microbiome produces a very large number of metabolites that enter the body and are part of the chemical exposome. It can metabolize xenobiotics and either eliminate them or lead to toxic derivatives. The complex interactions between chemicals of different origins will be illustrated by the diverse roles of the aryl hydrocarbon receptor which binds and transduces the signals of a large number of xenobiotics, microbiome metabolites, dietary chemicals and endogenous compounds. This article is part of the theme issue ‘Endocrine responses to environmental variation: conceptual approaches and recent developments’.

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“…Of note, the AHR is expressed across many different human tissues and mediates both inflammatory and antiinflammatory regulatory mechanisms, which often depends on the biological context (e.g., type of ligands, time of activation). 10 For instance, the AHR is involved in the differentiation and polarization of T cell subpopulations. It has been described for CD4 + T-cells and CD4 + TH-17cells that activation of the AHR mediates the (trans-)differentiation into anti-inflammatory, regulatory T cells (Tregs) 11 .…”

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confidence: 99%

Acute exercise increases systemic kynurenine pathway metabolites and activates the AHR in human PBMCs

Joisten,

Walzik,

Schenk

et al. 2024

Preprint

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The kynurenine pathway of tryptophan degradation generates several metabolites such as kynurenine or kynurenic acid that serve as endogenous ligands of the aryl hydrocarbon receptor (AHR). Due to its distinct biological roles particularly modulating the immune system, the AHR is a current therapeutic target across different inflammation-related diseases. Here, we show an exercise-induced increase in AHR ligand availability on a systemic level and a kynurenine pathway activation in peripheral mononuclear blood cells (PBMCs). Concurrently, the AHR is activated in PBMCs following acute exercise, with effects being dependent on exercise intensity. In conclusion, these data indicate a novel mechanistic link how exercise modulates the immune system through the kynurenine pathway-AHR axis, potentially underlying exercise-induced benefits in various chronic diseases.

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The complex biology of aryl hydrocarbon receptor activation in cancer and beyond

Cited by 16 publications

References 268 publications

The MTORC1-AHR pathway sustains translation and autophagy in tumours under tryptophan stress

The MTORC1-AHR pathway sustains translation and autophagy in tumours under tryptophan stress

Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways

Acute exercise increases systemic kynurenine pathway metabolites and activates the AHR in human PBMCs

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