ST6Gal-I sialyltransferase confers cisplatin resistance in ovarian tumor cells

Journal of Ovarian Research

Susan L Bellis²  Charles N Landen¹  Elizabeth S Sztul²  John W Wright²  Amanda F Swindall²  Matthew J Schultz² 

[1] Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA

关键词: Glycosylation;    Apoptosis;    Ovarian cancer;    Cisplatin;    Sialic acid;   

Others  :  810766
DOI  :  10.1186/1757-2215-6-25

 received in 2013-02-11, accepted in 2013-03-29,  发布年份 2013

【 摘 要 】

Background

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. 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.

Methods

Tumor 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.

Results

We 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.

Conclusions

Receptor 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.

【 授权许可】

   
2013 Schultz et al.; licensee BioMed Central Ltd.

【 图 表 】

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