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Defective activations of STAT3 Ser727 and PKC isoforms lead to oncostatin M resistance in metastatic melanoma cells
Author(s) -
Lacreusette A.,
Barbieux Isabelle,
Nguyen JeanMichel,
Pandolfino MarieChristine,
Dréno Brigitte,
Jacques Yannick,
Godard Anne,
Blanchard Frédéric
Publication year - 2009
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2490
Subject(s) - oncostatin m , melanoma , cancer research , protein kinase b , stat protein , stat3 , signal transduction , medicine , biology , interleukin 6 , immunology , microbiology and biotechnology , cytokine
Abstract Stage III melanoma is refractory to common therapies and shows resistance to the anti‐proliferative activity of cytokines in vitro . We previously demonstrated that, for 30% of the metastatic melanoma cell lines, oncostatin M (OSM) resistance is due to the epigenetic silencing of its receptor OSMR β. Here we analyse, on a larger panel of short‐term cultures derived from melanoma‐invaded lymph nodes, other mechanisms potentially implicated in OSM resistance. For 18% of the cell lines, OSM resistance is associated with a phosphorylation defect of signal transducer and activator of transcription (STAT)3 on serine (Ser)727, in concordance with defects in the activation of various protein kinase C (PKC) isoforms, especially PKCδ. For 21% of the cell lines, OSM resistance is associated with a defect in the activation of Akt on Ser473. By the use of inhibitors, dominant negatives and small interfering (si)RNA, we show that the PKC–STAT3 Ser727, but not the Akt, pathway appears necessary for OSM anti‐proliferative activity. Moreover, we bring evidence that OSM or interleukin (IL)‐6, produced in lymph nodes and/or melanoma cells, could be involved in the establishment of OSM resistance during melanoma progression. These findings could be relevant for the prognosis and the treatment of stage III melanoma patients. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.