Reference : Interleukin-6-resistant melanoma cells exhibit reduced activation of STAT3 and lack o...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Interleukin-6-resistant melanoma cells exhibit reduced activation of STAT3 and lack of inhibition of cyclin E-associated kinase activity
Böhm, M. [> >]
Schulte, U. [> >]
Funk, J. O. [> >]
Raghunath, M. [> >]
Behrmann, Iris mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Kortylewski, M. [> >]
Heinrich, P. C. [> >]
Kues, T. [> >]
Luger, T. A. [> >]
Schwarz, T. [> >]
Journal of Investigative Dermatology
Nature Publishing Group
Yes (verified by ORBilu)
New York
[en] cdc25 Phosphatases ; Janus Kinase 1 ; Interleukin-6 ; Humans ; G1 Phase ; DNA-Binding Proteins ; Cyclins ; Cyclin-Dependent Kinases ; Cyclin-Dependent Kinase Inhibitor p27 ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclin-Dependent Kinase 2 ; Cyclin E ; Cell Cycle Proteins ; MAP Kinase Kinase 1 ; Melanoma ; Tyrosine ; Tumor Suppressor Proteins ; Tumor Cells, Cultured ; Trans-Activators ; Skin Neoplasms ; Signal Transduction ; STAT3 Transcription Factor ; Retinoblastoma Protein ; Protein-Tyrosine Kinases ; Protein-Serine-Threonine Kinases ; Phosphorylation ; Mitogen-Activated Protein Kinase Kinases ; CDC2-CDC28 Kinases
[en] Development of cytokine resistance is an important feature of melanoma cells during tumor progression. To study the mechanisms of interleukin-6 resistance, we examined an interleukin-6 sensitive (WM35) and an interleukin-6 unresponsive cell line (WM9). Interleukin-6 treatment resulted in rapid inhibition of cyclin-dependent kinase 2/cyclin E activity and accumulation of the hypophosphorylated retinoblastoma protein in WM35 but not in WM9 cells. In contrast to previous reports, no differences in the expression of the cyclin-dependent kinase 2 inhibitor p21Cip1/WAF1 upon interleukin-6 treatment were found in both cell lines. Interleukin-6-induced inhibition of cyclin-dependent kinase 2 was also not due to changes in protein expression of cyclin-dependent kinase 2, cyclin E, p27Kip1 and cdc25A, a phosphatase positively regulating cyclin-dependent kinase 2 activity. As it is established that interleukin-6 resistance of WM9 cells is not caused by differential interleukin-6 receptor expression, we studied whether this is due to defective interleukin-6 signaling in which activation of signal transducer and activator of transcription 3 is a critical step. WM9 cells showed reduced tyrosine phosphorylation, DNA binding, and delayed nuclear translocation of signal transducer and activator of transcription 3 as compared with WM35 cells. The kinase upstream of signal transducer and activator of transcription 3, Janus kinase 1, was constitutively tyrosine-phosphorylated in WM9 cells and did not respond to interleukin-6 with increased phosphorylation. As compared with WM35 cells, interleukin-6 treatment of WM9 cells was not paralleled by reduced activity of the mitogen-activated protein kinase kinase-1, which suppresses activation of signal transducer and activator of transcription 3. Our data suggest that resistance of advanced melanoma cells to interleukin-6 is associated with reduced inhibition of cyclin-dependent kinase 2, which appears to be a consequence of a complex alteration in interleukin-6 signal transduction.

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