Melittin induces Bcl-2 and caspase-3-dependent apoptosis through downregulation of Akt phosphorylation in human leukemic U937 cells.
Melittin (MEL), a major polypeptide in bee venom (BV), is known to inhibit proliferation and induce apoptosis in cancer cells. However, the molecular mechanisms involved in MEL-induced apoptosis have not been fully elucidated, especially in human leukemic cells. In the present study, we report that MEL induces apoptosis in leukemic U937 cells through downregulating Akt signal pathways. Furthermore, MEL-induced apoptosis was accompanied by downregulation of Bcl-2 and activation of caspase-3. The induction of apoptosis also was accompanied by the downregulation of the inhibitor of apoptosis protein (IAP) family proteins. Treatment of U937 cells with the caspase-3 inhibitor, z-DEVD-fmk, was capable of significantly restoring cell viability in MEL-treated cells. Additionally, the caspase-3 mediated apoptotic response was significantly attenuated in Bcl-2-overexpressing U937 cells treated with MEL. These results indicate that downregulation of Bcl-2 plays a major role in activation of caspase-3 following MEL exposure. MEL also triggered downregulation of Akt. LY294002 (an inhibitor of Akt) significantly decreased cell viability and increased the proportion of cells with sub-G1 phase DNA content. The results indicated that key regulators in MEL-induced apoptosis in human leukemic U937 cells include Bcl-2 and caspase-3, which are controlled through the Akt signaling pathway.
Moon
Dong-Oh
DO
Faculty of Applied Marine Science, Cheju National University, Jeju-si, Jeju Special Self-Governing Province 690-756, Republic of Korea.
Park
Sung-Yong
SY
Choi
Yung Hyun
YH
Kim
Nam Deuk
ND
Lee
Chan
C
Kim
Gi-Young
GY
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D008555:Melitten / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D020298:U937 Cells
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D008555:Melitten; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3