Investigation of the aryl hydrocarbon receptor and the intrinsic tumoral component of the kynurenine pathway of tryptophan metabolism in primary brain tumors
Abstract
Introduction
There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment.
Methods
We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites. In addition, we utilized commercially available small-molecules to pharmacologically modulate IDO1, IDO2, TDO2, and AhR in patient-derived glioma and meningioma cell lines (n = 9 each).
Results
We observed a positive trend between the grade of the tumor and the average immunohistochemical staining score for IDO1, IDO2, and TDO2, with TDO2 displaying the strongest immunostaining. AhR immunostaining was present in all grades of gliomas and meningiomas, with the greatest staining intensity noted in glioblastomas. Immunocytochemical staining showed a positive trend between nuclear localization of AhR and histologic grade in both gliomas and meningiomas, suggesting increased AhR activation with higher tumor grade. Unlike enzyme inhibition, AhR antagonism markedly diminished patient-derived tumor cell viability, regardless of tumor type or grade, following in vitro drug treatments.
Conclusions
Collectively, these results suggest that AhR may offer a novel and robust therapeutic target for a patient population with highly limited treatment options.
Keywords
Aryl hydrocarbon receptor Gliomas Meningiomas Primary patient-derived tumor cells Immunosuppressive kynurenine pathway Tryptophan metabolismNotes
Acknowledgements
The study was supported, in part, by the following Grants: 1F31CA210682-01A1 (A.R.G.) from the National Cancer Institute; 4T32CA009531-30 (A.R.G.) from the National Cancer Institute; R25GM058905 (A.R.G.) from the National Institute of General Medical Sciences; R01CA123451 (C.J. and S.M.) from the National Cancer Institute; the Fund for Medical Research and Education, Wayne State University School of Medicine (S.M.); a Strategic Research Initiative Grant from Karmanos Cancer Institute (S.M.); and The Office of the Vice President for Research, Wayne State University (S.M.). The Biobanking and Correlative Sciences Core is supported, in part, by the National Institute of Health Center Grant P30CA022453 to the Karmanos Cancer Institute at Wayne State University. We wish to thank the patients who graciously donated their tumor tissue for this study.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Supplementary material
References
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