6-Shogaol induces apoptosis in human leukemia cells through a process involving caspase-mediated cleavage of eIF2α.
BACKGROUND
6-Shogaol is a promising antitumor agent isolated from dietary ginger (Zingiber officinale). However, little is known about the efficacy of 6-shogaol on leukemia cells. Here we investigated the underlying mechanism of 6-shogaol induced apoptosis in human leukemia cells in vitro and in vivo.


METHODS
Three leukemia cell lines and primary leukemia cells were used to investigate the apoptosis effect of 6-shogaol. A shotgun approach based on label-free proteome with LC-CHIP Q-TOF MS/MS was employed to identify the cellular targets of 6-shogaol and the differentially expressed proteins were analyzed by bioinformatics protocols.


RESULTS
The present study indicated that 6-shogaol selectively induced apoptosis in transformed and primary leukemia cells but not in normal cells. Eukaryotic translation initiation factor 2 alpha (eIF2α), a key regulator in apoptosis signaling pathway, was significantly affected in both Jurkat and U937 proteome profiles. The docking results suggested that 6-shogaol might bind well to eIF2α at Ser51 of the N-terminal domain. Immunoblotting data indicated that 6-shogaol induced apoptosis through a process involving dephosphorylation of eIF2α and caspase activation-dependent cleavage of eIF2α. Furthermore, 6-shogaol markedly inhibited tumor growth and induced apoptosis in U937 xenograft mouse model.


CONCLUSIONS
The potent anti-leukemia activity of 6-shogaol found both in vitro and in vivo in our study make this compound a potential anti-tumor agent for hematologic malignancies.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. gaoning59@yahoo.com.cn.
Qun
Q
Liu
Yong-Bo
YB
Peng
Ping
P
Zhou
Lian-Wen
LW
Qi
Mu
M
Zhang
Ning
N
Gao
E-Hu
EH
Liu
Ping
P
Li
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D002396:Catechols; D015852:Eukaryotic Initiation Factor-2; C040115:shogaol; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7