Abstract LB-301: Galectin-3 contributes to melanoma metastasis by regulating Autotaxin through NFAT1

Abstract

Abstract Melanoma is the deadliest form of skin cancer in which patients with metastatic disease have a five year survival-rate of less than 10%. Recently the over expression of a beta galactoside binding protein, Galectin-3, has been correlated with metastatic melanoma. Yet its role in melanoma progression is not completely understood. We have previously demonstrated that silencing Galectin-3 in melanoma cell lines leads to decreased melanoma cell invasion and migration in vitro and inhibits tumor growth and metastasis in vivo via the regulation of VE-cadherin and IL-8. To determine whether Galectin-3 can enhance the expression of other genes involved in the metastatic phenotype, a cDNA microarray analysis was performed after silencing Galectin-3 in melanoma cell lines. One of the many genes down regulated after silencing Galectin-3 is the lysophospholipase D enzyme Autotaxin. Autotaxin expression enhances melanoma migration and invasion by converting Lysophosphatidylcholine (LPC) to Lysophosphatidic acid (LPA) within the tumor microenvironment. LPA binds to EDG family G-protein coupled receptors to initiate downstream signaling which drives invasion and metastasis. Here we show that Galectin-3 regulates Autotaxin expression at the transcriptional level. Moreover, silencing Galectin-3 decreases total protein expression of the transcription factor NFAT1 which reduces its binding to the Autotaxin promoter. This in turn decreases Autotaxin promoter activity and protein expression. Therefore, Galectin-3 is required to maintain NFAT1 protein expression which enhances Autotaxin transcription and induces angiogenesis, tumor growth, and metastasis of melanoma cells. This is the first report to connect Galectin-3 with Autotaxin and LPA synthesis along with assigning an important role for NFAT1 in melanoma metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-301. doi:1538-7445.AM2012-LB-301