Abstract
Cancer stem cells are distinguished from normal adult stem cells by their stemness without tissue homeostasis control. Glycosphingolipids (GSLs), particularly globo-series GSLs, are important markers of undifferentiated embryonic stem cells, but little is known about whether or not ceramide glycosylation, which controls glycosphingolipid synthesis, plays a role in modulating stem cells. Here, we report that ceramide glycosylation catalyzed by glucosylceramide synthase, which is enhanced in breast cancer stem cells (BCSCs) but not in normal mammary epithelial stem cells, maintains tumorous pluripotency of BCSCs. Enhanced ceramide glycosylation and globotriosylceramide (Gb3) correlate well with the numbers of BCSCs in breast cancer cell lines. In BCSCs sorted with CD44(+)/ESA(+)/CD24(-) markers, Gb3 activates c-Src/β-catenin signaling and up-regulates the expression of FGF-2, CD44, and Oct-4 enriching tumorigenesis. Conversely, silencing glucosylceramide synthase expression disrupts Gb3 synthesis and selectively kills BCSCs through deactivation of c-Src/β-catenin signaling. These findings highlight the unexploited role of ceramide glycosylation in selectively maintaining the tumorous pluripotency of cancer stem cells. It speculates that disruption of ceramide glycosylation or globo-series GSL is a useful approach to specifically target BCSCs specifically.
Highlights
Glucosylceramide synthase catalyzes ceramide glycosylation that regulates the synthesis of glycosphingolipids
In assessment of cell response to doxorubicin, we found that the half-maximal inhibitory concentration (IC50) value for doxorubicin in MCF-7/Dox cells was 30-fold (9.8 M versus 0.33 M; p Ͻ 0.001) higher than the MCF-7 breast adenocarcinoma cells or human MCF-12A mammary epithelial cells (Fig. 1A)
Our results clearly indicate that ceramide glycosylation catalyzed by GCS is important for Cancer stem cells (CSCs) in drug resistance and tumorigenesis
Summary
Glucosylceramide synthase catalyzes ceramide glycosylation that regulates the synthesis of glycosphingolipids. Silencing glucosylceramide synthase expression disrupts Gb3 synthesis and selectively kills BCSCs through deactivation of c-Src/-catenin signaling These findings highlight the unexploited role of ceramide glycosylation in selectively maintaining the tumorous pluripotency of cancer stem cells. Several cellular signals including Wnt, Notch, and Hedgehog have been reported to be implicated in the self-renewal ability and pluripotency of normal stem cells in mammary gland development or remodeling and of BCSCs in cancer pathogenesis (5, 16 –19). It is not clear how BCSCs, like other CSCs, maintain tumor pluripotency without tissue homeostasis control. We examined the correlation of ceramide glycosylation with BCSCs in drug resistance and tumorigenesis
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