Gene expression changes and signaling events associated with the direct antimelanoma effect of IFN-gamma.
IFN-gamma plays a role in the response to melanoma indirectly through its effect on the immune system and directly through its antiproliferative and proapoptotic effects on melanoma cells. To understand the molecular basis for the direct antimelanoma effect of IFN-gamma, we studied IFN-induced changes in gene expression and signaling among three human melanoma cell lines (DM6, DM93, and 501mel). These were resistant to the antimelanoma effect of IFN-alpha, and only DM6 cells exhibited growth inhibition and apoptosis with IFN-gamma. Through DNA microarray analysis, we found that the antimelanoma effect of IFN-gamma in DM6 was associated with the down-regulation of multiple genes involved in G-protein signaling and phospholipase C activation (including Rap2B and calpain 3) as well as the down-regulation of genes involved in melanocyte/melanoma survival (MITF and SLUG), apoptosis inhibition (Bcl2A1 and galectin-3), and cell cycling (CDK2). The antimelanoma effect of IFN-gamma was also associated with the up-regulation of the proapoptotic dependence receptor UNC5H2 and the Wnt inhibitor Dkk-1. Whereas both IFNs were able to activate Stat1 in all cell lines, the delayed activation of the extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinases occurred only in DM6 with IFN-gamma, and the effect of IFN-gamma on cell growth and survival as well as gene expression in DM6 was dependent on the coordinate activation of MEK1 and p38. These findings provide new insights into the signaling events and gene expression changes associated with growth inhibition and apoptosis in melanoma and may thereby assist in identifying new targets for the treatment of melanoma.
Gollob
Jared A
JA
Division of Medical Oncology and Transplantation, Department of Medicine, Duke University, Durham, NC, USA. gollo001@mc.duke.edu
Sciambi
Catherine J
CJ
Huang
Zhiqing
Z
Dressman
Holly K
HK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D051153:Wnt Proteins; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1