Abstract 1704: A role for glucosylceramide synthase in resistance to oxaliplatin in colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is the second leading cause of cancer deaths in the U.S. Nearly 25 percent of patients who present with CRC have already developed metastatic disease. While combination therapies for metastatic CRC have improved median survival times, most patients inevitably become resistant to chemotherapy. Chemoresistance is thus the major cause of treatment failure in CRC patients, and accordingly, the development of novel therapies aimed at overcoming chemoresistance is of paramount importance. Many commonly used chemotherapeutic agents act by inducing cell death by increasing cellular levels of the bioactive sphingolipid, ceramide. In addition to serving well-known structural functions in the cell membrane, sphingolipids are increasingly recognized as important cellular signaling molecules. Studies have demonstrated that human colorectal tumors contain decreased concentrations of ceramide in comparison to normal colonic mucosa. Furthermore, multi-drug resistant cancer cells often display an altered sphingolipid content, with the presence of increased levels of the pro-survival ceramide metabolites. In this study we have examined the role of the ceramide-metabolizing enzyme, glucosylceramide synthase (GCS), in the mechanism of resistance to oxaliplatin. These studies utilize a series of oxaliplatin-resistant isogenic colorectal cancer cell lines. While much evidence has been presented establishing the role of GCS in resistance to a variety of chemotherapeutic agents, a role for GCS in oxaliplatin resistance has yet to be examined. Our studies demonstrate that oxaliplatin-resistant CRC cell lines have ∼ 2-fold more GCS protein with increased levels of the pro-survival ceramide metabolite, glucosylceramide, in comparison to the parental cell lines. We further demonstrate that inhibition of GCS by either pharmacological inhibitors or an RNAi-mediated gene knockdown results in reduced cellular glucosylceramide levels, with a concomitant increased sensitivity towards oxaliplatin. Furthermore, inhibition of GCS causes a reversion of an observed epithelial-mesenchymal transition phenotype observed in oxaliplatin-resistant CRC cell lines. Our results may offer a possible strategy with which to augment chemotherapeutic drug effectiveness in CRC. 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 1704. doi:10.1158/1538-7445.AM2011-1704