Integration of glycosphingolipid metabolism and cell-fate decisions in cancer and stem cells: Review and hypothesis

Erhard Bieberich

Research output: Contribution to journalReview article

48 Citations (Scopus)

Abstract

The metabolism of glycosphingolipids is strictly regulated during the mitotic cell cycle. Before the G1-to-S transition, the ceramide and glucosylceramide concentration is elevated. Ceramide induces apoptosis synergistically with the pro-apoptotic protein prostate apoptosis response 4 (PAR-4) that may be asymmetrically inherited during cell division. Only one daughter cell dies shortly after mitosis, a mechanism we suggested to regulate the number of neural stem cells during embryonic development. The progeny cells, however, may protect themselves by converting ceramide to glucosylceramide and other glycosphingolipids. In particular, complex gangliosides have been found to sustain cell survival and differentiation. The cell cycle may thus be a turning point for (glyco)sphingolipid metabolism and explain rapid changes of the sphingolipid composition in cells that undergo mitotic cell-fate decisions. In the proposed model termed "Shiva cycle", progression through the cell cycle, differentiation, or apoptosis may rely on a delicate balance of (glyco)sphingolipid second messengers that modulate the retinoblastoma-dependent G1-to-S transition or caspase-dependent G1-to-apoptosis program. Ceramide-induced cell cycle delay at G0/G1 is either followed by ceramide-induced apoptosis or by conversion of ceramide to glucosylceramide, a proposed key regulatory rheostat that rescues cells from re-entry into a life/death decision at G1-to-S. We propose a mechanistic model for sphingolpid-induced protein scaffolds ("slip") that regulate cell-fate decisions and will discuss the biological consequences and pharmacological potential of manipulating the (glyco)sphingolipid-dependent cell fate program in cancer and stem cells.

Original languageEnglish (US)
Pages (from-to)315-327
Number of pages13
JournalGlycoconjugate Journal
Volume21
Issue number6
DOIs
StatePublished - Nov 10 2004

Fingerprint

Glycosphingolipids
Neoplastic Stem Cells
Ceramides
Stem cells
Metabolism
Sphingolipids
Cells
Glucosylceramides
Apoptosis
Cell Cycle
Cell Differentiation
Apoptosis Regulatory Proteins
Gangliosides
Reentry
Second Messenger Systems
Caspases
Neural Stem Cells
Retinoblastoma
Scaffolds
Mitosis

Keywords

  • ES cells
  • apoptosis
  • asymmetric cell division
  • cell-cycle arrest
  • ceramide
  • gangliosides
  • glycosphingolipids
  • self-renewal
  • sphingolipids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Integration of glycosphingolipid metabolism and cell-fate decisions in cancer and stem cells : Review and hypothesis. / Bieberich, Erhard.

In: Glycoconjugate Journal, Vol. 21, No. 6, 10.11.2004, p. 315-327.

Research output: Contribution to journalReview article

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