Abstract 2889: NF-κB inducing kinase modulates melanoma tumorigenesis by regulating pro-survival factors through β-catenin

Abstract

Abstract Nuclear factor-κB (NF-κB) contributes to the progression of many cancers due to its role in regulating the transcription of genes important for inflammation, proliferation, apoptosis, and survival. In melanoma, high NF-κB activity results from constitutive elevation of IKKβ activity, a major kinase of this pathway. Targeted deletion of IKKβ prevents Ras induced melanoma tumor formation in INK4a/ARF-/- mice, underscoring the importance of NF-κB in melanoma. We have demonstrated that the NF-κB inducing kinase (NIK) is elevated in many melanoma cell lines. To determine the role of NIK overexpression in melanoma, we knocked down NIK using shRNA in WM115 and Hs294T human melanoma cell lines. NIK knock-down melanoma cells exhibited increased apoptosis and decreased proliferation. Similarly, NIK depletion substantially decreased tumor burden of WM115 cells in a xenograft model. Analysis of gene expression microarray data suggests that NIK modulates expression of c-Myc, c-Met, CCND2 and CXCR4, genes which are crucial for melanoma progression. Consistent with the apoptotic phenotype of NIK knock-down melanoma cells, expression of survival factors, such as Bcl2, cIAP1 and survivin, were attenuated in NIK knock-down melanoma cells. Intriguingly, Bcl2 and survivin expression levels (mRNA and protein) were also diminished in NIK knock-out mouse embryonic fibroblasts (MEFs), suggesting that these pro-survival genes are under the regulation of NIK. However, NF-κB activity is not reduced in NIK knock down cells, possibly due to the compensatory activation of IKKβ. Thus, we explored the possibility that NIK affects expression of survival factors in a NF-κB independent manner. Our data suggest that NIK regulates subcellular localization of β-catenin and modulates expression of survival genes such as survivin. Our findings reveal a novel mechanism by which NIK modulates pro-survival genes and suggest that NIK may be a promising therapeutic target for melanoma malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2889. doi:10.1158/1538-7445.AM2011-2889