Defective activations of STAT3 Ser727 and PKC isoforms lead to oncostatin M resistance in metastatic melanoma cells.
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 OSMRbeta. 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 PKCdelta. 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.
Lacreusette
A
A
INSERM U892, Centre de Recherche en Cancérologie, Nantes F-44035, France. alinelacreusette@yahoo.fr
Barbieux
Isabelle
I
Nguyen
Jean-Michel
JM
Pandolfino
Marie-Christine
MC
Dréno
Brigitte
B
Jacques
Yannick
Y
Godard
Anne
A
Blanchard
Frédéric
F
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000473:pathology / Q000556:secondary*; D009367:Neoplasm Staging; D053683:Oncostatin M / Q000494:pharmacology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D015850:Interleukin-6; D007527:Isoenzymes; D050796:STAT3 Transcription Factor; D053683:Oncostatin M; D011493:Protein Kinase C