Abstract 1470: Depletion of glycosphingolipids with MBO-asGCS eliminates cancer cell metastasis

Abstract Tumor metastasis, particularly multi-organ metastasis often causes failure of cancer treatment. It is well-known that the interaction of tumor cells with extracellular matrix (ECM) determines the metastatic ability of cancer cells; however, it is not clear whether depletion of glycosphingolipids (GSLs), a major component of GSL-enriched microdomain on plasma membrane is an approach to eliminate tumor metastasis. Glucosylceramide synthase (GCS) that converts ceramide to glucosylceramide is a limiting enzyme controlling GSL synthesis. We found that overexpression of GCS enhanced metastatic ability of human breast cancer cells. In MCF-7/Dox cells, GCS protein levels were increased 39 folds and GCS activity were increased 2 folds, as compared to MCF-7 cells. The wound healing, Matrigel attachment and MMP-9 activity in MCF-7/Dox cells increased 1.5 folds, 3 folds, and 2 folds respectively compared to MCF-7 cells. Introduction of GCS gene overexpressed GCS protein and significantly increased wound healing and Matrigel attachment by 2 folds and cell invasion 1.5 folds in MCF-7 cells. MBO-asGCS is a mixed backbone oligonucleotide that substantially suppresses GCS expression. Silencing of GCS with MBO-asGCS (100 nM) decreased the wound healing by 2 folds, Matrigel attachment by 1.5 folds and cell invasion by 3 folds in MCF/Dox cells. These results were also observed in MCF-7/DOX cells treated with d-PDMP, a GCS inhibitor. Mechanistic study indicated that overexpression of GCS increased GSLs, particular globo-series GSLs and enhanced VEGF and uPA to promote the mobility, cellular attachment and invasion of cancer cells. As GCS overexpression is tightly associated with drug-resistant cancer cells, this study may suggest that depletion of GSLs with MBO-asGCS is an effective approach to eliminate the metastasis of cancers that even fail in conventional chemotherapy. 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 1470. doi:10.1158/1538-7445.AM2011-1470