ABSTRACT
Upregulated ß-galactoside α2,6-sialyltransferase I (ST6Gal-I) expression reportedly occurs in many cancers and is correlated with metastasis and poor prognosis. However, the mechanisms by which ST6GalI facilitates gastric cancer progression remain poorly understood. Trastuzumab is exclusively used in human epidermal growth factor receptor 2 (HER2)+ gastric cancers; however, most advanced HER2+ gastric cancers develop trastuzumab resistance. Herein, we identified HER2 as an ST6GalI substrate and showed that HER2 α2,6 sialylation confers protection against trastuzumabmediated apoptosis. SGC7901 cancer cell models in which ST6GalI was overexpressed or knocked down were constructed, revealing that ST6GalI overexpression induced high HER2 sialylation levels and increased cell viability and invasion compared to those in the vector cell line under serum starvation; ST6GalI knockdown had the opposite effects. ST6GalI overexpression also potentiated cell cycle arrest in the G2/S phase to reduce drug sensitivity. In addition, FACS analysis revealed that high ST6GalI levels increased resistance to trastuzumabinduced apoptosis, accompanied by decreased caspase3 levels. However, the ST6GalI knockdown cell line revealed increased caspase3 levels and evident apoptosis compared with those in the vector cell line. Although ST6GalI overexpression increased HER2 sialylation, corresponding to decreased HER2 phosphorylation, high α2,6sialylation enhanced Akt and ERK phosphorylation levels compared to those in the vector cell line; ST6GalI knockdown had the opposite effects. Collectively, these results implicated a functional role of ST6GalI in promoting tumor cell progression and trastuzumab resistance.
