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Bortezomib Relieves Immune Tolerance in Nasopharyngeal Carcinoma via STAT1 Suppression and Indoleamine 2,3-Dioxygenase Downregulation
- Source :
- Cancer Immunology Research. 5:42-51
- Publication Year :
- 2017
- Publisher :
- American Association for Cancer Research (AACR), 2017.
-
Abstract
- Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC). Patients with intermediate and advanced stage NPC receiving only radiotherapy have limited survival, so newer immunotherapeutic approaches are sought. The major impediment to better clinical outcomes is tumor immune tolerance. Indoleamine 2,3-dioxygenase (IDO), an IFNγ-inducible enzyme, is a major inducer of immune tolerance during tumor development; therefore, inhibition of the IDO pathway is an important modality for cancer treatment. We show that bortezomib, a proteasomal inhibitor, inhibited the pathways leading to STAT1 and IRF-1 activation, both of which are necessary for IDO expression. Bortezomib downregulated IFNγ-induced IDO expression via inhibition of STAT1 phosphorylation and nuclear translocation, thereby suppressing STAT1-driven IDO transcription in NPC cells. Bortezomib also promoted IκB-α phosphorylation-ubiquitination, which released NF-κB from IκB-α. However, the released NF-κB could not enter the nucleus to conduct its biological effects and accumulated in the cytoplasm. Negative feedback inhibited the transcription of NF-κB, which is important for activating IRF-1 expression. IDO expression is regulated by two important transcription factor binding sites, ISREs, which bind STAT1 and IRF-1, and GASs, which binds STAT1. Bortezomib upregulated IRF-1 protein by inhibiting its proteasome-dependent degradation, but it also inhibited STAT1 phosphorylation, which directly inhibited the activation of GAS and indirectly inhibited the activation of ISRE, which needs both STAT1 and IRF-1. These discoveries provide a mechanism for the antitumor action of bortezomib and have implications for the development of clinical cancer immunotherapy for preventing and treating NPC. Cancer Immunol Res; 5(1); 42–51. ©2016 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Cell Survival
medicine.medical_treatment
Immunology
Active Transport, Cell Nucleus
Antineoplastic Agents
Immune tolerance
Bortezomib
Interferon-gamma
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Cancer immunotherapy
Cell Line, Tumor
Immune Tolerance
medicine
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
STAT1
Phosphorylation
Indoleamine 2,3-dioxygenase
Nasopharyngeal Carcinoma
biology
Carcinoma
NF-kappa B
Nasopharyngeal Neoplasms
medicine.disease
Enzyme Activation
STAT1 Transcription Factor
030104 developmental biology
Nasopharyngeal carcinoma
030220 oncology & carcinogenesis
biology.protein
Cancer research
Protein Binding
medicine.drug
Subjects
Details
- ISSN :
- 23266074 and 23266066
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Cancer Immunology Research
- Accession number :
- edsair.doi.dedup.....d4cca8c1c82786e8e0ecb4022a4c470d