Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals.

Abstract:

:The sphingomyelin pathway, which is initiated by sphingomyelin hydrolysis to generate the second messenger ceramide, signals apoptosis for tumor necrosis factor alpha, Fas, and ionizing radiation. In the present studies, the anticancer drug daunorubicin also stimulated ceramide elevation and apoptosis in P388 and U937 cells. Cell-permeable analogs of ceramide, but not other lipid second messengers, mimicked daunorubicin in inducing apoptosis. Daunorubicin-stimulated ceramide elevation, however, did not result from sphingomyelin hydrolysis, but rather from de novo synthesis via activation of the enzyme ceramide synthase. An obligatory role for ceramide synthase was defined, since its natural specific inhibitor, fumonisin B1, blocked daunorubicin-induced ceramide elevation and apoptosis. These studies demonstrate that ceramide synthase activity can be regulated in eukaryotes and constitute definitive evidence for a requirement for ceramide elevation in the induction of apoptosis.

journal_name

Cell

journal_title

Cell

authors

Bose R,Verheij M,Haimovitz-Friedman A,Scotto K,Fuks Z,Kolesnick R

doi

10.1016/0092-8674(95)90429-8

subject

Has Abstract

pub_date

1995-08-11 00:00:00

pages

405-14

issue

3

eissn

0092-8674

issn

1097-4172

pii

0092-8674(95)90429-8

journal_volume

82

pub_type

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