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SHR Neuro Cancer Cardio Lipid Metab Microb

Krejsgaard, T; Vetter-Kauczok, CS; Woetmann, A; Lovato, P; Labuda, T; Eriksen, KW; Zhang, Q; Becker, JC; Odum, N.
Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma.
Leukemia. 2006; 20(10):1759-1766 Doi: 10.1038/sj.leu.2404350 [OPEN ACCESS]
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Co-authors Med Uni Graz: Becker Jürgen Christian
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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.
Find related publications in this database (using NLM MeSH Indexing): Cell Line, Tumor -; Curcumin - pharmacology; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Neoplastic -; Humans -; Hypoxia-Inducible Factor 1, alpha Subunit - genetics Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; JNK Mitogen-Activated Protein Kinases - antagonists and inhibitors JNK Mitogen-Activated Protein Kinases - genetics JNK Mitogen-Activated Protein Kinases - metabolism; Janus Kinase 3 -; Lymphoma, T-Cell - metabolism Lymphoma, T-Cell - physiopathology Lymphoma, T-Cell - therapy; Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - physiopathology Neovascularization, Pathologic - therapy; Protein-Tyrosine Kinases - antagonists and inhibitors Protein-Tyrosine Kinases - genetics Protein-Tyrosine Kinases - metabolism; RNA, Messenger - metabolism; STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism; Skin Neoplasms - metabolism Skin Neoplasms - physiopathology Skin Neoplasms - therapy; Sp1 Transcription Factor - genetics Sp1 Transcription Factor - metabolism; Sp3 Transcription Factor - genetics Sp3 Transcription Factor - metabolism; Transcription Factor AP-1 - genetics Transcription Factor AP-1 - metabolism; Transcription Factor AP-2 - genetics Transcription Factor AP-2 - metabolism; Transfection -; Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism
Find related publications in this database (Keywords): CTCL; VEGF; Jak3; JNK; curcumin; angiogenesis