title: Ceramide glycosylation by glucosylceramide synthase selectively maintains the properties of breast cancer stem cells.
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.
authors.affiliation: Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, Louisiana 71209, USA.
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
authors.forename: Kaustubh N
authors.initials: KN
authors.lastname: Bhinge
authors.forename: Salman B
authors.initials: SB
authors.lastname: Hosain
authors.forename: Katherine
authors.initials: K
authors.lastname: Xiong
authors.forename: Xin
authors.initials: X
authors.lastname: Gu
authors.forename: Runhua
authors.initials: R
authors.lastname: Shi
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Ho
authors.forename: Kay-Hooi
authors.initials: KH
authors.lastname: Khoo
authors.forename: Su-Chen
authors.initials: SC
authors.lastname: Li
authors.forename: Yu-Teh
authors.initials: YT
authors.lastname: Li
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: S Michal
authors.initials: SM
authors.lastname: Jazwinski
authors.forename: Yong-Yu
authors.initials: YY
authors.lastname: Liu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D051927:CD24 Antigen / Q000378:metabolism; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002518:Ceramides / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005964:Glucosyltransferases / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D018189:Immunomagnetic Separation; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D002518:Ceramides; D018960:Hyaluronan Receptors; D051176:beta Catenin; D004317:Doxorubicin; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase