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Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma.
- Source :
-
Leukemia (08876924) . Oct2006, Vol. 20 Issue 10, p1759-1766. 8p. 7 Graphs. - Publication Year :
- 2006
-
Abstract
- Biopsies from patients with cutaneous T-cell lymphoma (CTCL) exhibit stage-dependent increase in angiogenesis. However, the molecular mechanisms responsible for the increased angiogenesis are unknown. Here we show that malignant CTCL T cells spontaneously produce the potent angiogenic protein, vascular endothelial growth factor (VEGF). Dermal infiltrates of CTCL lesions show frequent and intense staining with anti-VEGF antibody, indicating a steady, high production of VEGF in vivo. Moreover, the VEGF production is associated with constitutive activity of Janus kinase 3 (Jak3) and the c-Jun N-terminal kinases (JNKs). Sp600125, an inhibitor of JNK activity and activator protein-1 (AP-1) binding to the VEGF promoter, downregulates the VEGF production without affecting Jak3 activity. Similarly, inhibitors of Jak3 inhibit the VEGF production without affecting JNK activity. Downregulation of Stat3 with small interfering RNA has no effect, whereas curcumin, an inhibitor of both Jak3 and the JNKs, almost completely blocks the VEGF production. In conclusion, we provide evidence of VEGF production in CTCL, which is promoted by aberrant activation of Jak3 and the JNKs. Inhibition of VEGF-inducing pathways or neutralization of VEGF itself could represent novel therapeutic modalities in CTCL. [ABSTRACT FROM AUTHOR]
- Subjects :
- *BIOPSY
*DIAGNOSTIC specimens
*T cells
*LYMPHOMAS
*NEOVASCULARIZATION
*VASCULAR endothelial growth factors
*HEMATOPOIETIC growth factors
*VASCULAR endothelium
*RNA
*PRECANCEROUS conditions
*PROTEIN metabolism
*RNA metabolism
*TREATMENT of skin tumors
*CARRIER proteins
*CELL lines
*COMPARATIVE studies
*ENZYME inhibitors
*GENES
*GENETIC techniques
*RESEARCH methodology
*MEDICAL cooperation
*PROTEIN-tyrosine kinases
*PROTEINS
*RESEARCH
*SKIN tumors
*TRANSFERASES
*EVALUATION research
*CURCUMIN
*T-cell lymphoma
*PATHOLOGIC neovascularization
*CHEMICAL inhibitors
*PHARMACODYNAMICS
*METABOLISM
*THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 08876924
- Volume :
- 20
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- Leukemia (08876924)
- Publication Type :
- Academic Journal
- Accession number :
- 22741209
- Full Text :
- https://doi.org/10.1038/sj.leu.2404350