Influence of Bcl-2 overexpression on the ceramide pathway in daunorubicin-induced apoptosis of leukemic cells.

Abstract:

:We have previously demonstrated that daunorubicin (DNR) induces apoptosis in some leukemic myeloid cell lines. We investigated a potential protective role for Bcl-2 in apoptosis induced by DNR in two leukemic cell lines, one myeloid and one lymphoid, overexpressing the anti-apoptotic gene Bcl-2. Parental cells treated with DNR exhibited classical features of apoptosis 6 h after drug exposure, all the cells being dead after 30-48 h. In contrast, overexpression of Bcl-2 significantly delayed, but did not prevent the occurrence of DNR-induced apoptosis, with no surviving cells 96 h after drug exposure. To elucidate the mechanism of the protection mediated by Bcl-2, we explored the signaling pathway which initiates DNR-induced apoptosis. In this report, we show that, in both the myeloid and lymphoid parental cell lines, DNR triggered a sphingomyelin (SM) hydrolysis after 10-15 min with a concomitant ceramide generation. Moreover, exogenous ceramide induced DNA fragmentation in these cells, with levels similar to those observed with DNR treatment. In contrast, Bcl-2 overexpression protected the cells against apoptosis induced by ceramide treatment, without preventing the early SM hydrolysis nor the ceramide generation in these cells. Our results strongly suggest that Bcl-2-mediated protection of DNR-induced apoptosis is effected downstream of the SM-ceramide signaling pathway.

journal_name

Oncogene

journal_title

Oncogene

authors

Allouche M,Bettaieb A,Vindis C,Rousse A,Grignon C,Laurent G

doi

10.1038/sj.onc.1201023

subject

Has Abstract

pub_date

1997-04-17 00:00:00

pages

1837-45

issue

15

eissn

0950-9232

issn

1476-5594

journal_volume

14

pub_type

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