Diosgenin, a plant steroid, induces apoptosis in COX-2 deficient K562 cells with activation of the p38 MAP kinase signalling and inhibition of NF-kappaB binding.
Diosgenin is a steroidal sapogenin with antitumor properties. We previously showed that diosgenin induced apoptosis in human erythroleukemia (HEL) cells. In order to elucidate the mechanism of its apoptotic activity, we investigated the effect of diosgenin on nuclear factor-kappaB (NF-kappaB) binding and on three groups of human mitogen-activated protein kinases (MAPKs) in relation to diosgenin-induced apoptosis in different erythroleukemia cell lines (K562 and HEL). Our results showed that diosgenin decreased DNA binding of NF-kappaB in K562 and HEL cells after 48-h diosgenin treatment. This inhibition of NF-kappaB binding was correlated with strong apoptosis in both erythroleukemia cell lines. Diosgenin-induced apoptosis was associated with cyclo-oxygenase-2 (COX-2) up-regulation in HEL cells but not in K562 cells which are COX-2 deficient. Furthermore, diosgenin inhibited extracellular signal-regulated kinase (ERK) activation only in HEL cells. However, diosgenin activated p38 MAPK in both cell lines and activated c-jun NH2-terminal kinases (JNKs) only in HEL cells. Pre-treatment with a selective p38 inhibitor inhibited diosgenin-induced DNA fragmentation in K562 cells. For the first time, our results suggest that inhibition of NF-kappaB nuclear binding and p38 MAPK activation are involved in the diosgenin-mediated signal cascades in K562 cells for inducing/regulating DNA fragmentation.
Liagre
Bertrand
B
Laboratoire de Biochimie, UPRES EA 1085, Faculté de Pharmacie, 87025 Limoges Cedex, France. bertrand.liagre@unilim.fr
Bertrand
Julian
J
Leger
David Y
DY
Beneytout
Jean-Louis
JL
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004144:Diosgenin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020014:K562 Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010840:Phytosterols / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D007093:Imidazoles; D016328:NF-kappa B; D010840:Phytosterols; D011725:Pyridines; D051546:Cyclooxygenase 2; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D004144:Diosgenin; C093642:SB 203580