Abstract
BackgroundPlatinum drugs, including cisplatin, are a frontline therapeutic in ovarian cancer treatment and acquired resistance to these agents is a major contributor to ovarian cancer morbidity and mortality. In this study a novel glycosylation-dependent mechanism for cisplatin resistance is described. Specifically, cisplatin-induced cell death is blocked by the activity of the ST6Gal-I sialyltransferase. ST6Gal-I modifies specific receptors by adding a negatively charged sialic acid sugar which influences diverse receptor functions. Overexpression of ST6Gal-I is a hallmark of ovarian and other cancers and its expression has been correlated to metastasis and poor prognosis.MethodsTumor cell viability and apoptotic induction were determined in cell lines with ST6Gal-I overexpression and knockdown. In addition, cell populations with acquired resistance to cisplatin were assayed for endogenous ST6Gal-I expression.ResultsWe show that forced expression of ST6Gal-I in OV4 ovarian cancer cells that lack endogenous ST6Gal-I causes reduced activation of caspase 3 and increased cell viability following cisplatin treatment. Conversely, forced ST6Gal-I knockdown in Pa-1 cells with high endogenous ST6Gal-I increases cisplatin-induced caspase activation and cell death. A2780 ovarian cancer cells selected for stable cisplatin resistance display upregulated endogenous ST6Gal-I when compared with parental, cisplatin-sensitive, A2780 cells. Similarly, extended low dose cisplatin treatment of a Pa-1 polyclonal ST6Gal-I shRNA knockdown population led to selection for subclones with elevated ST6Gal-I expression.ConclusionsReceptor sialylation by ST6Gal-I confers a survival advantage for tumor cells in the presence of cisplatin. These collective findings support a role for ST6Gal-I in chemoresistance and highlight ST6Gal-I as a potential therapeutic target for platinum resistant tumors.
Highlights
Platinum drugs, including cisplatin, are a frontline therapeutic in ovarian cancer treatment and acquired resistance to these agents is a major contributor to ovarian cancer morbidity and mortality
Forced overexpression of ST6Gal-I confers tumor cell resistance to cisplatin-induced apoptosis In order to evaluate the effects of receptor α2-6 sialylation on tumor cell sensitivity to cisplatin, we utilized cell models with engineered ST6Gal-I expression
It is known that platinum drugresistant cells have abnormal glycosylation [29,30], and studies spanning more than two decades indicate that cisplatin treatment alters the sialic acid content of tumor cells [31,32,33]
Summary
Platinum drugs, including cisplatin, are a frontline therapeutic in ovarian cancer treatment and acquired resistance to these agents is a major contributor to ovarian cancer morbidity and mortality. Cisplatin-induced cell death is blocked by the activity of the ST6Gal-I sialyltransferase. ST6Gal-I modifies specific receptors by adding a negatively charged sialic acid sugar which influences diverse receptor functions. Overexpression of ST6Gal-I is a hallmark of ovarian and other cancers and its expression has been correlated to metastasis and poor prognosis. The β-galactoside α2-6-sialyltransferase ST6Gal-I catalyzes the addition of the negatively-charged sugar, sialic acid, to the termini of N-linked glycans on selected cell surface or secreted proteins as they transit through the Golgi. Depending on the specific substrate targeted by ST6Gal-I, α2-6 sialylation can modulate observations suggest that ST6Gal-I may play a role in regulating the complement of receptors on the cell surface, in addition to modulating the function of distinct glycoproteins through effects on receptor conformation and/ or clustering. ST6Gal-I activity is associated with resistance to radiation treatment [20]
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