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Cytokine signalling in human melanoma cells determines susceptability to statin-induced apoptosis
BMC Pharmacology
Meeting abstract Cytokine signalling in human melanoma cells determines susceptability to statin-induced apoptosis Christoph Minichsdorfer and Martin Hohenegger*
0 Address: Institute of Pharmacology, Center for Biomolecular Medicine and Pharmacology, Medical University of Vienna , 1090 Vienna , Austria
<supplement><title><p>15thScientifcSymposiumoftheAustrianPharmacologicalSociety(APHAR)</p></title><editor>AndreaLaslopandThomasGriesbacher</editor><note>Me tingabstracts-AsinglePDFcontainingal abstractsinthisSupplementisavailable<ahref="htp:/www.biomedcentral.com/content/files/pdf/1471-2210-9-S2-ful.pdf">here</a>.</note><url>htp:/www.biomedcentral.com/content/pdf/1471-2 10-9-S2-info.pdf</url></supplement> This abstract is available from: http://www.biomedcentral.com/1471-2210/9/S2/A28 References 1. Minichsdorfer C, Hohenegger M: Autocrine amplification loop in statin-induced apoptosis of human melanoma cells. Br J Pharmacol 2009, 157:1278-1290.
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from 15th Scientific Symposium of the Austrian Pharmacological Society (APHAR) Joint meeting with the Hungarian Society of Experimental and Clinical
Pharmacology (MFT) and the Slovenian Pharmacological Society (SDF)
Graz, Austria. 19-21 November 2009
Background
Melanoma is one of the most aggressive and
chemoresistant cancer types in humans. Especially in late stages,
effective therapeutic approaches are not available. Statins have
been investigated for their anti-proliferative and
proapoptotic effects in many tumor cells including
melanoma [1]. Beside paracrine signalling, melanoma
cells rely on a wide range of autocrine cytokine loops.
Methods and results
We have therefore screened the serum-free supernatant of
simvastatin-treated 518A2 melanoma cells for cytokines.
While INF-γ, TNF-α, IL-1α, IL-1β, IL-10 and IL-12 were
not regulated by simvastatin, most strikingly, IL-6 levels
were significantly decreased. IL-6 is an important
prognostic marker in late stage melanoma. Due to this crucial
role in the autocrine regulation of the tumour growth this
cytokine was investigated in greater detail. A375 and
518A2 melanoma cells were transfected with a fluorescent
Stat-3 fusion protein and showed IL-6-mediated
translocation of Stat-3-YFP into the nucleus. This was followed
by a transient phosphorylation of Stat-3. Conversely, the
''IL-6-insensitive'' melanoma cell lines, WM278 and
WM793B, showed constitutively active Stat-3
phosphorylation and virtually no regulation upon IL-6 addition.
Interestingly, the latter cells were approximately 10-fold
less susceptible toward statin-induced caspase 3 activation
compared to A375 and 518A2 melanoma cells. Moreover,
addition of IL-6 to simvastatin-treated A375 and 518A2
melanoma cells abrogated the pro-apoptotic effect of
statins.
Conclusion
Taken together, theses data may open a possible new
therapeutic window for statins in late-stage melanoma
therapy which is based on IL-6 suppression by simvastatin in
the metastatic melanoma cell lines A375 and 518A2,
while early-stage melanoma cell lines, WM278 and
WM793B were virtually insensitive to statin treatment. (...truncated)