Chemotherapy resistance is a significant clinical obstacle in the treatment of cancer. Platinum-based drugs are a mainstay of treatment in many solid cancers; however, tumor resistance to these drugs hampers long term efficacy. Resistance is multi-factorial, and theories to explain resistance are incomplete. In this study we report a novel mechanism for resistance to cisplatin involving changes in receptor glycosylation. Previous work in our lab has demonstrated enhanced colon cancer cell survival in cells expressing ST6Gal-I, a Golgi glycosyltransferase that adds the negatively-charged sugar, alpha2-6-linked sialic acid, to selected membrane proteins. We showed that sialylation of the Fas death receptor by ST6Gal-I decreases apoptotic signaling in response to Fas agonists by blocking DISC formation and receptor internalization. Elevated ST6Gal-I expression has been reported in many cancers, including ovarian and colon, and its expression is negatively correlated with patient prognosis. Interestingly, cisplatin has been demonstrated to mediate its cytotoxic effects, in part, through Fas receptor upregulation and activation, although the mechanism is not currently understood. Combining these results and observations, we investigated whether ST6Gal-I-mediated sialylation of the Fas receptor inhibits apoptotic signaling in response to cisplatin treatment, contributing to intrinsic cisplatin resistance. We determined the extent of cisplatin-induced apoptotic cell death by blotting for cleaved caspase-3, a terminal caspase, and detected decreased levels of activated caspase in ST6Gal-I expressing ovarian and colon cell lines. This result was observed in both a low endogenous ST6Gal-I cell model with forced ST6Gal-I expression, as well as a high endogenous ST6Gal-I expression cell model with shRNA ST6Gal-I knockdown. We also show sustained viability in cells expressing ST6Gal-I after cisplatin treatment by measuring a peptide protease substrate which is cleaved in live cells. Conversely, we detected a decrease in viability in non-ST6Gal-I expressing counterpart cell lines indicating that cells lacking ST6Gal-I expression are more sensitive to cisplatin-mediated cell death. Finally, we observed that cisplatin-mediated cell death is attenuated by treating cells with blocking antibodies to Fas, consistent with other studies implicating this receptor in cisplatin efficacy. Our findings suggest a novel mechanism contributing to platinum drug resistance in cancer cell populations and identify ST6Gal-I as a promising target for therapeutic intervention.

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 4899. doi:1538-7445.AM2012-4899