title: Regulation of death and growth signals at the plasma membrane by sphingomyelin synthesis: implications for hematological malignancies.
abstract: Resistance to death receptor ligands (such as FasL and TRAIL) and anticancer treatments is a hallmark of cancer cells. Ceramide, a biologically active sphingolipid, antagonizes cell growth and promotes apoptosis and non-apoptotic forms of cell death. The intracellular levels of ceramide are highly regulated via complex metabolic pathways. Sphingomyelin synthases (SMS) 1 and 2 convert ceramide to sphingomyelin (SM), a ubiquitous phospholipid in mammals. A growing body of evidence in the literature indicates that SMSs likely modulate hematological cell growth and sensitivity to stress-induced apoptosis. On one hand, complete and sustained inhibition of SMS activity is likely to alter membrane composition and properties through membrane SM depletion, perturbing intracellular signaling pathways and leukemia cell growth and conferring partial resistance to death receptor ligands. On the other hand, different patents & reports point to anti-apoptotic functions for SMSs. In patients with chemoresistant leukemia, a decreased intracellular ceramide level was associated with a higher SMS activity. Thus, SMSs and cofactors may constitute original pharmacological targets to treat leukemia.
authors.affiliation: INSERM UMR1037-Cancer Research Center of Toulouse, BP84225, 31432 Toulouse Cedex 4, France. bruno.segui@inserm.fr
authors.forename: Elodie
authors.initials: E
authors.lastname: Lafont
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kitatani
authors.forename: Toshiro
authors.initials: T
authors.lastname: Okazaki
authors.forename: Bruno
authors.initials: B
authors.lastname: Ségui
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation; D019337:Hematologic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology; D013109:Sphingomyelins / Q000096:biosynthesis* / Q000502:physiology
chemical_list: D013109:Sphingomyelins