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Tryptophan‐2,3‐dioxygenase is regulated by prostaglandin E2 in malignant glioma via a positive signaling loop involving prostaglandin E receptor‐4
Author(s) -
Ochs Katharina,
Ott Martina,
Rauschenbach Katharina J.,
Deumelandt Katrin,
Sahm Felix,
Opitz Christiane A.,
Deimling Andreas,
Wick Wolfgang,
Platten Michael
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13503
Subject(s) - glioma , cancer research , prostaglandin e2 receptor , prostaglandin e2 , gene knockdown , prostaglandin e , signal transduction , receptor , immune system , prostaglandin , malignant transformation , biology , kynurenine , chemistry , tryptophan , endocrinology , cell culture , microbiology and biotechnology , biochemistry , immunology , amino acid , agonist , genetics
Malignant gliomas and other types of tumors generate a local immunosuppressive microenvironment, which prohibits an effective anti‐tumor immune response and promotes tumor growth. Along with others, we have recently demonstrated that catabolism of the essential amino acid tryptophan via tryptophan‐2,3‐dioxygenase ( TDO ) is an important mechanism mediating tumor‐associated immunosuppression particularly in gliomas. The pathways regulating TDO in tumors, however, are poorly understood. Here, we show that prostaglandins enhance TDO expression and enzymatic activity in malignant gliomas via activation of prostaglandin E receptor‐4 ( EP 4). Stimulation with prostaglandin E 2 ( PGE 2 ) up‐regulated TDO ‐mediated kynurenine release in human glioma cell lines, whereas knockdown of the PGE 2 receptor EP 4 inhibited TDO expression and activity. In human malignant glioma tissue expression of the PGE 2 ‐producing enzyme cyclooxygenase‐2 ( COX 2) and its receptor EP 4 were associated with TDO expression both on transcript and protein level. High expression of EP 4 correlated with poor survival in malignant glioma patients WHO III ‐ IV . Importantly, treatment of glioma cells with an EP 4 inhibitor decreased TDO expression and activity. Moreover, TDO ‐over‐expressing murine gliomas showed increased COX 2 and EP 4 expression suggesting a positive feedback mechanism in vivo . In summary, targeting EP 4 may inhibit – in addition to immunosuppressive COX 2 signaling – tryptophan degradation as another important immunosuppressive pathway and thus, could provide a dual clinically relevant immunotherapeutic avenue for the treatment of malignant gliomas.We proposed that in malignant gliomas prostaglandin E 2 (PGE 2 ) produced by cyclooxygenases (COX) up‐regulates tryptophan‐2,3‐dioxygenase (TDO) expression and enzyme activity through binding to its Gs‐coupled receptor EP4 and therefore may mediate tumor immune escape in part through aryl hydrocarbon receptor (AHR) activation. Moreover, TDO activity itself seems to induce intratumoral PGE 2 metabolism suggesting an immunosuppressive loop involving COX/EP4/TDO.