title: Fludarabine downregulates indoleamine 2,3-dioxygenase in tumors via a proteasome-mediated degradation mechanism.
abstract: Indoleamine 2,3-dioxygenase (IDO) is found in multiple malignancies and exerts immunosuppressive effects that are central in protecting tumors from host T lymphocyte rejection. IDO is an enzyme involved in the catabolism of tryptophan resulting in inhibition of T lymphocyte function. While inhibition of IDO enzymatic activity results in tumor rejection, it is still unknown how we can directly target IDO expression within tumors using drugs. We have chosen to interfere with IDO expression by targeting the key-signaling event signal transducer and activator of transcription 1 (STAT1). We evaluated the efficacy of fludarabine, previously described to inhibit STAT1 phosphorylation. Interestingly, fludarabine was efficient in suppressing protein expression and consequently IDO activity in two different cell lines derived from breast cancer and melanoma when IDO was activated with interferon-gamma (IFN-γ) or supernatants prepared from activated T lymphocytes. However, fludarabine had no inhibitory effect on STAT1 phosphorylation. Other IFN-γ-responsive genes were only marginally inhibited by fludarabine. The level of IDO transcript was unaffected by this inhibitor, suggesting the involvement of post-transcriptional control. Strikingly, we have found that the inhibition of proteasome partially protected IDO from fludarabine-induced degradation, indicating that fludarabine induces IDO degradation through a proteasome-dependent pathway. Currently used in the clinic to treat some malignancies, fludarabine has the potential for use in the treatment of human tumors through induction of IDO degradation and consequently, for the promotion of T cell-mediated anti-tumor response.
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: Laïla-Aïcha
authors.initials: LA
authors.lastname: Hanafi
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauchat
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Godin-Ethier
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Possamaï
authors.affiliation: Centre de recherche en infectiologie, Centre hospitalier universitaire de Québec and Department of Microbiology, Infectiology and Immunology, Université Laval, Québec, Québec, Canada; PROTEO, Université Laval, Québec, Québec, Canada.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Duvignaud
authors.affiliation: Centre de recherche en infectiologie, Centre hospitalier universitaire de Québec and Department of Microbiology, Infectiology and Immunology, Université Laval, Québec, Québec, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Leclerc
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM) and Departement of Biochemistry, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Grandvaux
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada.
authors.forename: Réjean
authors.initials: R
authors.lastname: Lapointe
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D060890:B7-H1 Antigen / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D015395:Histocompatibility Antigens Class I; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex; D014740:Vidarabine; C024352:fludarabine