Fludarabine Downregulates Indoleamine 2,3-Dioxygenase in Tumors via a Proteasome-Mediated Degradation Mechanism

Autor: Réjean Lapointe, Jean-Baptiste Duvignaud, David Possamaï, Nathalie Grandvaux, Dominique Gauchat, Laïla-Aïcha Hanafi, Jessica Godin-Ethier, Denis Leclerc
Jazyk: angličtina
Rok vydání: 2014
Předmět:
T-Lymphocytes
Cancer Treatment
lcsh:Medicine
Biochemistry
B7-H1 Antigen
White Blood Cells
0302 clinical medicine
Animal Cells
Medicine and Health Sciences
Tumor Cells
Cultured
Interferon gamma
STAT1
Phosphorylation
RNA
Small Interfering
Indoleamine 2
3-dioxygenase
lcsh:Science
0303 health sciences
Multidisciplinary
biology
Protein Stability
Hematology
3. Good health
Fludarabine
Enzymes
STAT1 Transcription Factor
Oncology
030220 oncology & carcinogenesis
RNA Interference
Immunotherapy
Cellular Types
Vidarabine
medicine.drug
Research Article
Tumor Immunology
Proteasome Endopeptidase Complex
Immunology
Down-Regulation
Antineoplastic Agents
Immunomodulation
03 medical and health sciences
Interferon-gamma
Downregulation and upregulation
medicine
Humans
Indoleamine-Pyrrole 2
3
-Dioxygenase
RNA
Messenger
030304 developmental biology
Blood Cells
lcsh:R
Histocompatibility Antigens Class I
Immunity
Biology and Life Sciences
Cell Biology
Proteasome
biology.protein
STAT protein
Cancer research
Enzymology
lcsh:Q
Clinical Immunology
Zdroj: PLoS ONE
PLoS ONE, Vol 9, Iss 6, p e99211 (2014)
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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