Abstract
Background6-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.MethodsThree 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.ResultsThe 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.ConclusionThe 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.
Highlights
In recent years, the use of natural dietary agents has become widely accepted as a realistic option for the treatment of malignant cancers because of their cost-effectiveness and wide safety margin. 6-Shogaol, a major pungent ingredient in ginger (Zingiber officinale Roscoe, Zingiberaceae), has attracted great attention due to its considerable pharmacologic effects including anti-cancer, anti-inflammatory, antioxidant, as well as antiemetic properties [1,2,3,4]
Our results showed that cleavage of Eukaryotic translation initiation factor 2 alpha (eIF2α) and phosphoeIF2α by caspase activation may contribute to 6-shogaolmediated cell death in human leukemia cells
6-shogaol had little or no effect on expression of ATF6, IRE1 and phospho-IRE1. These findings demonstrate that PERK-eIF2α related endoplasmic reticulum (ER) stress pathway could play an important role in 6-shogaolinduced apoptosis in leukemia cells
Summary
The use of natural dietary agents has become widely accepted as a realistic option for the treatment of malignant cancers because of their cost-effectiveness and wide safety margin. 6-Shogaol, a major pungent ingredient in ginger (Zingiber officinale Roscoe, Zingiberaceae), has attracted great attention due to its considerable pharmacologic effects including anti-cancer, anti-inflammatory, antioxidant, as well as antiemetic properties [1,2,3,4]. Previous studies on the role of signaling cascades in 6shogaol-related lethality have primarily focused on reactive oxygen species (ROS) production, activation of caspase, GADD 153 expression, tubulin polymerization, AKT/ mTOR and matrix metalloproteinase 9 (MMP-9) expression [5,6,9,11]. The compound was reported to inhibit breast cancer cell invasion by reducing MMP-9 expression via targeting the NF-kB activation cascade [9] or by inhibiting invade podium formation [12]. Despite enormous efforts performed to investigate the anticancer activities of 6-shogaol, to date, the study on induction of apoptosis induced by 6-shogaol in human leukemia cells has not yet been explored, nor have the relationships between 6-shogaol-mediated anti-leukemic activity and cell signaling cascades been examined in depth. In particular the shotgun approach by label-free LC-CHIP Q-TOF MS/MS allows the qualitative and quantitative analysis of complex samples
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