Acquired STAT4 deficiency as a consequence of cancer chemotherapy

Autor: Jeffrey B. Travers, Hua Chen Chang, Michael J. Robertson, Manuel De La Rosa, Kinnari Oza, Ling Han, Allysia Schwartz, Ivan P. Lupov, Ravi P. Sahu, David Pelloso, Larry Voiles
Rok vydání: 2011
Předmět:
Skin Neoplasms
Lymphoma
RNA Stability
medicine.medical_treatment
Gene Expression
Biochemistry
Bortezomib
Mice
Autologous stem-cell transplantation
immune system diseases
Drug Interactions
skin and connective tissue diseases
Melanoma
STAT4
Cells
Cultured
Etoposide
hemic and immune systems
Hematology
STAT4 Transcription Factor
Flow Cytometry
Boronic Acids
Interleukin-12
medicine.anatomical_structure
Pyrazines
medicine.drug
musculoskeletal diseases
Immunology
Antineoplastic Agents
Biology
Natural killer cell
medicine
Animals
Humans
Antineoplastic Agents
Alkylating
Immunobiology
Chemotherapy
Ubiquitin
Cell Biology
Immunotherapy
medicine.disease
Antineoplastic Agents
Phytogenic
Carmustine
Mice
Inbred C57BL
Protein Biosynthesis
Leukocytes
Mononuclear
Cancer research
Proteasome inhibitor
Interleukin-2
Zdroj: Blood. 118:6097-6106
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2011-03-341867
Popis: Signal Transducer and Activator of Transcription 4 (STAT4) is a transcription factor that is activated by IL-12 signaling and promotes Th1-cell differentiation and IFN-γ production. Defective IFN-γ production because of STAT4 mRNA and protein deficiency occurs after autologous stem cell transplantation for lymphoma. In the present study, we investigated the mechanisms of STAT4 deficiency in lymphoma patients. The tumor-bearing state is not responsible, because STAT4 levels were not significantly different in PBMCs obtained from healthy control subjects compared with those from lymphoma patients before treatment. STAT4 protein levels were significantly decreased in PBMCs and T cells obtained from lymphoma patients after standard-dose chemotherapy. Furthermore, treatment of control PBMC cultures or a natural killer cell line with chemotherapy drugs in vitro also resulted in reduced STAT4 protein and diminished, IL-12–induced IFN-γ production. Translation of STAT4 protein was not impaired in chemotherapy-treated cells, whereas the STAT4 protein half-life was significantly reduced. Chemotherapy drugs promoted the ubiquitination and proteasomal degradation of STAT4. Treatment with the proteasome inhibitor bortezomib reversed chemotherapy-induced STAT4 deficiency and defective IFN-γ production. We conclude that acquired STAT4 deficiency in lymphoma patients is a consequence of treatment with chemotherapy, results that have important implications for the design of optimal immunotherapy for lymphoma.
Databáze: OpenAIRE
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