Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma

TY - JOUR

T1 - Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma

AU - Krejsgaard, T

AU - Vetter-Kauczok, C S

AU - Woetmann, A

AU - Lovato, P

AU - Labuda, T

AU - Eriksen, K W

AU - Zhang, Q

AU - Becker, J C

AU - Odum, N

N1 - Keywords: Cell Line, Tumor; Curcumin; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; JNK Mitogen-Activated Protein Kinases; Janus Kinase 3; Lymphoma, T-Cell; Neovascularization, Pathologic; Protein-Tyrosine Kinases; RNA, Messenger; STAT3 Transcription Factor; Skin Neoplasms; Sp1 Transcription Factor; Sp3 Transcription Factor; Transcription Factor AP-1; Transcription Factor AP-2; Transfection; Vascular Endothelial Growth Factor A

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1038/sj.leu.2404350

DO - 10.1038/sj.leu.2404350

M3 - Journal article

C2 - 16932349

SN - 0887-6924

VL - 20

SP - 1759

EP - 1766

JO - Leukemia

JF - Leukemia

IS - 10

ER -