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Activation of c-Jun NH₂-Terminal Kinase/Stress-activated Protein Kinase (JNK/SAPK) Is Critical for Hypoxia-induced Apoptosis of Human Malignant Melanoma¹

Department of Dermatology and Venereology [M. K., G. G.] and Institute of Immunology [S. I., D. K., H-J. T., H. J. K.], University of Rostock, 18055 Rostock, Germany; Department of Neuropathology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany [T. A., K. H. P.]; Institut für Medizinische Strahlenkunde und Zellforschung [S. L., U. R. R.] and Department of Dermatology [E-B. B.], University of Würzburg, 97080 Würzburg, Germany; Department of Pathology, University of Nijmegen, 6500 Nijmegen, the Netherlands [G. N. P. v. M.]; and Paul-Ehrlich-Institute, 63225 Langen, Germany [E. F.]

Mitogen-activated protein kinase (MAPK) signaling was examined in malignant melanoma cells exposed to hypoxia. Here we demonstrate that hypoxia induced a strong activation of the c-Jun NH₂-terminal kinase (JNK), also termed stress-activated protein kinase (SAPK), in the melanoma cell line 530 in vitro. Other members of the MAPK family, e.g., extracellular signal-regulated kinase and p38, remained unaffected by the hypoxic stimulus. Activated JNK/SAPK could also be observed in the vicinity of hypoxic tumor areas in melanoma metastases as detected by immunohistochemistry. Functional analysis of JNK/SAPK activation in the melanoma cell line 530 revealed that activation of JNK/SAPK is involved in hypoxia-mediated tumor cell apoptosis. Both a dominant negative mutant of JNK/SAPK (SAPKß KR) and a dominant negative mutant of the immediate upstream activator of JNK/SAPK, SEK1 (SEK1 KR), inhibited hypoxia-induced apoptosis in transient transfection studies. In contrast, overexpression of the wild-type kinases had a slight proapoptotic effect. Inhibition of extracellular signal-regulated kinase and p38 pathways by the chemical inhibitors PD98058 and SB203580, respectively, had no effect on hypoxia-induced apoptosis. Under normoxic conditions, no influence on apoptosis regulation was observed after inhibition of all three MAPK pathways. In contrast to recent findings, JNK/SAPK activation did not correlate with Fas or Fas ligand (FasL) expression, suggesting that the Fas/FasL system is not involved in hypoxia-induced apoptosis in melanoma cells. Taken together, our data demonstrate that hypoxia-induced JNK/SAPK activation appears to play a critical role in apoptosis regulation of melanoma cells in vitro and in vivo, independent of the Fas/FasL system.

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