Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt.
Bee venom (BV) has been known to inhibit proliferation and induce apoptosis in cancer cells. However, the molecular mechanisms involved in BV-induced apoptosis are still uncharacterized in human leukemic cells. In the present study, we report that BV induces apoptosis in leukemic U937 cells through downregulation of ERK and Akt signal pathway. Furthermore, BV-induced apoptosis was accompanied by downregulation of Bcl-2, activation of caspase-3 and a subsequent poly(ADP-ribose)polymerase (PARP) cleavages. The induction of apoptosis also was accompanied by the downregulation of the inhibitor of apoptosis protein (IAP) family proteins. Caspase-3 inhibitor, z-DEVD-fmk, was significantly capable of restoring cell viability and BV-induced apoptosis through caspase-3 activation was significantly attenuated in Bcl-2-overexpressing cells. These results indicate that downregulation of Bcl-2 plays a major role in the initiation as an activator of a caspase-3 involved with BV-induced apoptosis. BV also triggered the activation of p38 MAPK and JNK, and downregulation of ERK and Akt. PD98059 (an inhibitor of ERK) or LY294002 (an inhibitor of Akt), but not an inhibitor of p38 MAPK and JNK, significantly decreased cell viability and increased lactate dehydrogenase (LDH) release. The results indicated that key regulators in BV-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of the ERK and Akt signal pathway.
Moon
Dong-Oh
DO
Faculty of Applied Marine Science, Cheju National University, Jeju, South Korea.
Park
Sung-Yong
SY
Heo
Moon-Soo
MS
Kim
Ki-Cheon
KC
Park
Cheol
C
Ko
Woo Shin
WS
Choi
Yung Hyun
YH
Kim
Gi-Young
GY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001514:Bee Venoms / Q000494:pharmacology*; D001854:Bone Marrow Cells; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D024161:Collagen Type XI / Q000378:metabolism; D053938:DNA Fragmentation; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020298:U937 Cells
D001514:Bee Venoms; C499319:COL11A2 protein, human; D024161:Collagen Type XI; D019253:Proto-Oncogene Proteins c-bcl-2; D007770:L-Lactate Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3