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Gene Expression Changes and Signaling Events Associated with the Direct Antimelanoma Effect of IFN-

¹ Division of Medical Oncology and Transplantation, Department of Medicine, Duke University; ² Division of Hematology and Oncology, Geriatrics Research, Education and Clinical Center, Department of Medicine, Durham VA Medical Center; and ³ Department of Molecular Genetics and Microbiology, Center for Genome Technology, Duke Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina

Requests for reprints: Jared A. Gollob, Duke University Medical Center, DUMC Box 3441, Durham, NC 27710. Phone: 919-668-3979; Fax: 919-668-2163; E-mail: gollo001{at}mc.duke.edu.

IFN- 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-, 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-, and only DM6 cells exhibited growth inhibition and apoptosis with IFN-. Through DNA microarray analysis, we found that the antimelanoma effect of IFN- 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- 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-, and the effect of IFN- 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.

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