Posted September 30, 2014
Dr. Susan Bellis
The survival rates for ovarian cancer patients have not improved significantly over the past three decades; ovarian cancer remains the most deadly gynecologic malignancy. Many patients that initially respond to treatment will eventually develop tumor recurrence and succumb to chemotherapy-resistant disease. It has long been understood that the cell surface glycans of many different types of tumor cells are altered, but it was unclear what role these alterations played in cancer. In an effort to uncover the pathways responsible for these alterations, Dr. Susan Bellis, an FY10 OCRP Pilot Award recipient and her group are studying the enzyme ST6Gal-I and its role in sialylation, the process of adding a sialic acid (a negatively charged sugar molecule) to selected cell surface receptors or secreted glycoproteins (secreted proteins with a carbohydrate attached). These studies may uncover novel molecular pathways to target when developing new treatments for ovarian cancer.
Dr. Bellis' group has identified ST6Gal-I as a regulator of the ovarian cancer phenotype. They found that ST6Gal-I is overexpressed in the vast majority of ovarian serous adenocarcinomas and associated metastases. The Bellis group showed that ovarian cancer cells are able to evade cell death within the peritoneal milieu by the addition of sialic acids to certain cell surface receptors in a process mediated by ST6Gal-I. In addition, they determined that ST6Gal-I provides an advantage to tumor cells through several molecular pathways. Using ST6Gal-I overexpression or shRNA-mediated knockdown in ovarian and colon cancer cells, they have established that sialylation of β1 integrin promotes tumor cell migration and invasion through a collagen-rich extra cellular matrix. Also, Dr. Bellis' group showed that ST6Gal-I-dependent sialylation of the Fas and TNFR1 death receptors blocks apoptotic signaling. These findings suggest that the upregulation of ST6Gal-I and subsequent ST6Gal-I mediated sialylation contribute to the invasive and apoptosis resistant phenotype of ovarian cancer cells. These modifications of receptor function appear to drive a malignant phenotype.
These studies are critical to understanding the strong effects of sialylation in preventing apoptotic signaling in cancer cells. Further studies are underway to pursue ST6Gal-I as a biomarker for ovarian cancer and a potential therapeutic target.
Schultz MJ, Swindall AF, and Bellis SL. 2012. Regulation of the metastatic cell phenotype by sialylated glycans. Cancer Metastasis Rev 31:501-518.
Swindall AF, Londono-Joshi AI, Schultz MJ, et al. 2013. ST6Gal-I protein expression is upregulated in human epithelial tumors and correlates with stem cell markers in normal tissues and colon cancer cell lines. Cancer Res 73:2368-2378.
Schultz MJ, Swindall AF, Wright JW, et al. 2013. ST6Gal-I sialyltransferase confers cisplatin resistance in ovarian tumor cells. J Ovarian Res 6:25.
Swindall AF and Bellis SL. 2011. Sialylation of the Fas death receptor by ST6Gal-I provides protection against Fas-mediated apoptosis in colon carcinoma cells. J Biol Chem 286:22982-22990.