TY - JOUR
T1 - Regulation of death and growth signals at the plasma membrane by sphingomyelin synthesis
T2 - Implications for hematological malignancies
AU - Lafont, Elodie
AU - Kitatani, Kazuyuki
AU - Okazaki, Toshiro
AU - Ségui, Bruno
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
KW - Cancer
KW - Cell death
KW - Cell proliferation
KW - Ceramide
KW - Sphingolipids
KW - Sphingomyelin synthase
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U2 - 10.2174/157489211796957801
DO - 10.2174/157489211796957801
M3 - Article
C2 - 21762071
AN - SCOPUS:80052341977
VL - 6
SP - 324
EP - 333
JO - Recent Patents on Anti-Cancer Drug Discovery
JF - Recent Patents on Anti-Cancer Drug Discovery
SN - 1574-8928
IS - 3
ER -