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6-Shogaol Induces Apoptosis in Human Leukemia Cells Through A

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6-Shogaol Induces Apoptosis in Human Leukemia Cells Through A Liu et al. Molecular Cancer 2013, 12:135 http://www.molecular-cancer.com/content/12/1/135 RESEARCH Open Access 6-Shogaol induces apoptosis in human leukemia cells through a process involving caspase-mediated cleavage of eIF2α Qun Liu1†, Yong-Bo Peng1†, Ping Zhou1, Lian-Wen Qi1, Mu Zhang1, Ning Gao2*, E-Hu Liu1* and Ping Li1* Abstract 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. Conclusion: 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. Keywords: 6-shogaol, Leukemia, Apoptosis, Shotgun proteome, eIF2α Background apoptosis in a variety of cancer cells including human lung In recent years, the use of natural dietary agents has be- cancer, colorectal carcinoma, hepatocarcinoma, ovarian come widely accepted as a realistic option for the treatment cancer and breast cancer cells [5-10]. of malignant cancers because of their cost-effectiveness and Previous studies on the role of signaling cascades in 6- wide safety margin. 6-Shogaol, a major pungent ingredient shogaol-related lethality have primarily focused on reactive in ginger (Zingiber officinale Roscoe, Zingiberaceae), has oxygen species (ROS) production, activation of caspase, attracted great attention due to its considerable pharma- GADD 153 expression, tubulin polymerization, AKT/ cologic effects including anti-cancer, anti-inflammatory, mTOR and matrix metalloproteinase 9 (MMP-9) expres- antioxidant, as well as antiemetic properties [1-4]. Eviden- sion [5,6,9,11]. The compound was also reported to inhibit ces have revealed that 6-shogaol could induce cell death/ breast cancer cell invasion by reducing MMP-9 expression viatargetingtheNF-kB activation cascade [9] or by inhib- * Correspondence: [email protected]; [email protected]; iting invade podium formation [12]. Our group and Gan [email protected] et al. have found that 6-shogaol induced G2/M cell cycle † Equal contributors arrest and apoptosis characterized by caspase 3 and PARP 1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China cleavage in HeLa and HCT116 cells [3,13]. Despite enor- 2Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical mous efforts performed to investigate the anticancer University, Chongqing 400038, China © 2013 Liu et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Liu et al. Molecular Cancer 2013, 12:135 Page 2 of 12 http://www.molecular-cancer.com/content/12/1/135 activities of 6-shogaol, to date, the study on induction of To determine whether these events were restricted to apoptosis induced by 6-shogaol in human leukemia cells myeloid leukemia cells, parallel studies were performed has not yet been explored, nor have the relationships in other leukemia cell lines including U937 and HL-60 between 6-shogaol-mediated anti-leukemic activity and cell leukemia cells. These cells exhibited apoptotic effects of 6- signaling cascades been examined in depth. shogaol similar to those observed in Jurkat cells (Figure 1d). Cell apoptosis involves two distinct pathways, the death Also, U937 and HL-60 cells caused comparable degrees of receptor-initiated extrinsic pathway and the mitochondria- caspase-7 and caspase-3 activation and PARP degradation mediated intrinsic pathway [14,15]. Recent studies point to (Figure 1e). endoplasmic reticulum (ER) as a third subcellular compart- To determine whether 6-shogaol could also trigger ment implicated in apoptotic execution [16,17]. Disruption apoptosis in primary human leukemia cells, primary of any function of ER causes ER stress and activates a leukemia cells isolated from 7 leukemia patients were cytoprotective signaling cascade called unfolded protein treated without or with 10 and 20 μM 6-shogaol for response (UPR) [18]. Different stimuli signal through 24 h, after which apoptosis were determined by Annexin several protein kinases to up-regulate the protein folding V/PI staining and flow cytometry. Exposure of cells to 6- capacity of the ER through UPR induces the expression of shogaol resulted in pronounced increase in apoptosis in ER chaperones such as GRP78/BiP [19]. Nowadays, the primary leukemia peripheral blood mononuclear cells proteomic platform represents a powerful tool for profiling (Figure 1f). In contract, the 6-shogaol regimen had no the comprehensive protein expression and investigation of or little effect on apoptosis in normal bone marrow the apoptotic mechanism of drugs. In particular the shot- mononuclear cells (Figure 1g). Together, these findings gun approach by label-free LC-CHIP Q-TOF MS/MS indicate that 6-shogaol selectively kills transformed allows the qualitative and quantitative analysis of complex and primary human leukemia cells but not normal samples. hematopoietic cells. In the present study, we examined the apoptotic effects of 6-shogaol on three different leukemia cell lines Proteins alternation of leukemia cells in response to and primary leukemia patients cells. A shotgun proteo- 6-shogaol treatment by LC-CHIP Q-TOF MS/MS mics strategy based on LC-CHIP Q-TOF MS/MS was To get insights into the mechanism of apoptosis induced used to identify and quantify the differentially-expressed by 6-shogaol, an integrated proteomic-bioinformatics proteins of control and 6-shogaol-treated leukemia cells. platform was used to investigate the global protein Our results showed that cleavage of eIF2α and phospho- profiles of control and 6-shogaol-treated leukemia cells. eIF2α by caspase activation may contribute to 6-shogaol- In order to highlight the main proteome alterations in mediated cell death in human leukemia cells. Our in vivo leukemia cells in response to 6-shogaol exposure, we results indicate that induction of apoptosis may contribute generated protein expression profiles of two cell lines to 6-shogaol-mediated inhibitory effects on tumor growth (Jurkat and U937) by a label-free shotgun proteomic of U937 xenograft mouse model. These findings provide a approach after 12 h treatment with vehicle control (0.1% novel mechanistic basis for 6-shogaol as a leukemia treat- DMSO) or 15 μM 6-shogaol. The average peptide spec- ment strategy. tral intensity was used as a standard to normalize and compare the relative protein abundance in control and Results 6-shogaol treated cells [20,21]. More than 800 proteins 6-Shogaol potently induced apoptosis in transformed and were identified in our experiments. The identification of primary human leukemia cells, but not in normal bone proteins with remarkable differences (up- or down- marrow mononuclear cells regulated over 2.0-fold) in Jurkat and U937 cells were Flow cytometry analysis revealed that treating Jurkat shown in Additional file 1: Table S1 and Additional file cells with 2.5 and 5 μM 6-shogaol for 24 h resulted in a 2: Table S2. The regulated proteins were listed by their moderate increase in apoptosis. These events became protein name, accession number of SWISSPROT, abbre- apparent at 10 μM and very extensive at 15 μM concen- viations, MW/pI and fold change. trations (Figure 1a). A time-course study of cells exposed In the present study, all significantly modulated pro- to 15 μM 6-shogaol revealed a moderate increase in teins were functionally categorized using the PANTHER apoptosis as early as 6 h after drug exposure. These Classification System (http://pantherdb.org) (As indica- events became apparent after 12 h of drug exposure and ted in Figure 2a and 2b), the majority of differentially reached near-maximal levels after 24 h of drug exposure expressed proteins identified were in the categories of (Figure 1b). Consistent with these findings, the same 6- binding, catalytic activity, structural molecule activity, shogaol concentrations and exposure intervals caused enzyme regulator activity and transcription regulator cleavage/activation of caspase-3 and caspase-7, as well as activity in both Jurkat and U937 cells. We also note that PARP degradation (Figure 1c). some differentially expressed proteins in the categories Liu et al. Molecular Cancer 2013, 12:135 Page 3 of 12 http://www.molecular-cancer.com/content/12/1/135 Figure 1 6-Shogaol induces apoptosis in transformed and primary leukemia cells. Cells apoptosis was determined using Annexin V/PI staining by flow cytometry. The values obtained from Annexin V/PI represent the mean±SD for three separate experiments. The difference were significant at *p < 0.05, **p < 0.01. (a) Jurkat cells were treated without or with various concentrations of 6-shogaol (6S) for 24 h. (b) Jurkat cells were treated without or with 15 μM for different time intervals as indicated.
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