The phosphoinositide 3-kinase/Akt pathway is activated by daunorubicin in human acute myeloid leukemia cell lines.
Daunorubicin induces apoptosis in myeloid leukemia cells by activation of neutral sphingomyelinase and ceramide generation occurring 4-10 min after daunorubicin addition. We show here that daunorubicin is able to increase the phosphoinositide 3-kinase activity and enhance intracellular phosphoinositide 3-kinase lipid products prior to ceramide generation. Daunorubicin activates Akt, a downstream phosphoinositide 3-kinase effector. Interestingly, the phosphoinositide 3-kinase inhibitors wortmannin and LY294002 accelerate daunorubicin-induced apoptosis in U937 cells. The phosphoinositide 3-kinase/Akt pathway has been involved in cell survival following serum deprivation, tumor necrosis factor alpha, anti-Fas and UV radiations. Our results suggest that anti-tumor agents such as daunorubicin may also activate anti-apoptotic signals that could contribute to drug resistance.
Plo
I
I
INSERM E9910, Institut Claudius Rëguad, Toulouse, France.
Bettaïeb
A
A
Payrastre
B
B
Mansat-De Mas
V
V
Bordier
C
C
Rousse
A
A
Kowalski-Chauvel
A
A
Laurent
G
G
Lautier
D
D
D000208:Acute Disease; D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis; D002518:Ceramides / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D007951:Leukemia, Myeloid; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D020298:U937 Cells; D000077191:Wortmannin
D000730:Androstadienes; D002518:Ceramides; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D018129:Phosphatidylinositol Phosphates; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D000077191:Wortmannin; D003630:Daunorubicin