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Research Article Cucurbitacin E Induces G2/M Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2012, Article ID 952762, 11 pages doi:10.1155/2012/952762 Research Article Cucurbitacin E Induces G2/M Phase Arrest through STAT3/p53/p21 Signaling and Provokes Apoptosis via Fas/CD95 and Mitochondria-Dependent Pathways in Human Bladder Cancer T24 Cells Wen-Wen Huang, 1 Jai-Sing Yang,2 Meng-Wei Lin,1 Po-Yuan Chen,1 Shang-Ming Chiou,3 Fu-Shin Chueh,4 Yu-Hsuan Lan, 5 Shu-Jen Pai,1 Minoru Tsuzuki,6, 7 Wai-Jane Ho, 8 and Jing-Gung Chung1, 9 1 Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan 2 Department of Pharmacology, China Medical University, Taichung 404, Taiwan 3 Department of Functional Neurosurgery and Gamma Knife Center, China Medical University Hospital, Taichung 404, Taiwan 4 Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan 5 School of Pharmacy, China Medical University, Taichung 404, Taiwan 6 Department of Biochemistry, Nihon Pharmaceutical University, Saitama 362-0806, Japan 7 Tsuzuki Institute for Traditional Medicine, China Medical University, Taichung 404, Taiwan 8 Department of Medicinal Botanicals and Health Care, Da-Yeh University, Changhua 515, Taiwan 9 Department of Biotechnology, Asia University, Taichung 413, Taiwan Correspondence should be addressed to Jing-Gung Chung, [email protected] Received 31 May 2011; Revised 25 September 2011; Accepted 2 October 2011 Academic Editor: Jae Youl Cho Copyright © 2012 Wen-Wen Huang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cucurbitacin E, a tetracyclic triterpenes compound extracted from cucurbitaceous plants, has been shown to exhibit anticancer and anti-inflammatory activities. The purpose of this study was to elucidate whether cucurbitacin E promotes cell cycle arrest and induces apoptosis in T24 cells and further to explore the underlying molecular mechanisms. The effects of cucurbitacin E on T24 cell’s growth and accompanied morphological changes were examined by MTT assay and a phase-contrast microscope. DNA content, mitochondrial membrane potential (ΔΨm) and annexin V/PI staining were determined by flow cytometry. The protein levels were measured by Western blotting. Our results demonstrated that cucurbitacin E-induced G2/M arrest was associated with a marked increase in the levels of p53, p21 and a decrease in phospho-signal transducer and activator of transcription 3 (STAT3), cyclin-dependent kinase 1 (CDK1) and cyclin B. Cucurbitacin E-triggered apoptosis was accompanied with up-regulation of Fas/CD95, truncated BID (t-BID) and a loss of ΔΨm, resulting in the releases of cytochrome c, apoptotic protease activating factor 1 (Apaf-1) and apoptosis-inducing factor (AIF), and sequential activation of caspase-8, caspase-9, and caspase-3. Our findings provided the first evidence that STAT3/p53/p21 signaling, Fas/CD95 and mitochondria-dependent pathways play critical roles in cucurbitacin E-induced G2/M phase arrest and apoptosis of T24 cells. 1. Introduction the Taiwan Department of Health annual reports 2009, bladder cancer is 14th leading cause of cancer death in In 2008, approximately 37500 new bladder cancer cases Taiwanese men and about three persons per one hundred were diagnosed worldwide [1]. In the United States, approx- thousand die annually from that. Today, bladder cancer is imately 68,810 people and 14,100 deaths from bladder usually treated with surgery, chemotherapy, and combina- cancer were reported in 2008 alone [1]. According to tion of chemotherapy and radiotherapy, but they are often 2 Evidence-Based Complementary and Alternative Medicine 120 intolerable because of the strong systemic toxicity and local 24 h irritation [2]. Therefore, the finding for a novel adjuvant 100 agent to treat bladder cancer that can reduce the recurrence a 80 rate, decrease side effects, and increase overall survival is a, b, c urgent. In the past ten years, investigators have focused 60 a, b, c, d on plant food-derived phytochemicals to find potential 40 anticancer drugs [3, 4]. Approximately 70% of the currently (%) Viability approved anticancer drugs are derived from or based on 20 naturalproducts[5]. Cucurbitacin E (molecular formula: 0 C32H44O8) is a natural flavonoid found in Cucurbitaceae 0 250 500 1000 2000 but also presents in other plants [6–8] and traditional Cucurbitacin E (nM) Chinese herbal medicine such as Cucurbita pepo cv dayangua (a) [9]. Cucurbitacin E has been reported to exhibit bio- 120 logical activities, including antioxidant, anti-inflammatory, 48 h and anticancer effects [6, 9, 10]. Cucurbitacin E induced 100 a cytotoxic effects, including suppression of the proliferation 80 a and induction of apoptosis in ovarian [11, 12], leukemia [13, 60 a, b, c 14], and pancreatic [15] cancer cell lines. Cucurbitacin E also 40 suppressed tumor angiogenesis through interacting vascular- (%) Viability a, b, c, d endothelial-growth-factor-receptor-2-(VEGFR2-) mediated 20 Janus kinase 2 (Jak2)-signal transducer and activator of tra- 0 nscription 3 (STAT3) signals [9]. 0 250 500 1000 2000 It is well documented that apoptosis plays an important Cucurbitacin E (nM) role in the maintenance of tissue homeostasis for the elimination of excessive cells [16]. However, it is also well (b) known that the induction of apoptosis of cancer cells by Figure 1: The chemical structure of cucurbitacin E and its effects anticancer drugs such as etoposide, cisplatin, and paclitaxel of cell viability on human bladder cancer T24 cells. Cells were has been used for treatment of cancer in target cells [17–20]. treated with different concentrations of cucurbitacin E for 24 h Many reports have shown that numerous cytotoxic and DNA (a) and 48 h (b) and then cells were harvested for calculated the damaging agents could arrest the cell cycle at the G1, S, or percentage of viable cells as described in the Materials and Methods. ± P ≤ . G /M phase and induce apoptotic cell death [21–23]which Data are presented as mean S.D. in triplicate. a, 0 05, 2 is significant different compared with the DMSO-treated control; is involved in downregulation of phosphorylated STAT3, an b, c and d, P ≤ 0.05, are significant different with 250, 500 oncogene that has a vital role at all stages of tumorigenesis and 1000 nM of cucurbitacin E treatment, respectively, by one-way [15]. Therefore, the present study investigated the induction ANOVA followed by Bonferroni’s test for multiple comparisons. of apoptosis by cucurbitacin E in human bladder cancer cells, and we also attempted to clarify the possible signaling pathways involved in cucurbitacin E-induced apoptosis. Our Taiwan) and was cultured with McCoy’s 5a medium supple- results indicated cucurbitacin E induced G /M phase arrest 2 mented with 10% FBS, 100 Units/mL penicillin, 100 μg/mL and apoptosis in human bladder cancer T24 cells through ◦ streptomycin, and 2 mM L-glutamine at 37 Cunderahu- STAT3/p53/p21, Fas/CD95, and mitochondria-dependent midified 5% CO and 95% air at one atmosphere. The me- pathways. 2 dium was changed every 2 days [24]. 2. Material and Methods 2.3. Determinations of Cell Morphology and Viability. About 2 × 105 T24 cells/well were seeded into 12-well plates for 2.1. Chemicals and Reagents. Cucurbitacin E, dimethyl sul- cell adherence with three wells for each concentration level. foxide (DMSO), propidium iodide (PI), 3-(4,5-Dimethylthi- Cucurbitacin E was individually added to the final concen- azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), RNase trations of 0, 250, 500, 1000, and 2000 nM, respectively. In A, and Triton X-100 were purchased from Sigma-Aldrich control group, equal amount of 1% DMSO was added, while Corp. (St. Louis, MO, USA). All primary and secondary an- in blank control group, only culture medium was added tibodies were obtained from Santa Cruz Biotechnology Inc. to each well. In the end of incubation for 24 or 48 h, cells (Santa Cruz, CA, USA). The fluorescent probe DiOC6 and all from each well were examined and photographed under a culture media and reagents were purchased from Invitrogen phase-contrast microscope at 200× magnification and then Life Technologies (Carlsbad, CA, USA). cell viability was determined using the MTT method, as described previously [25, 26]. 2.2. Cell Culture. The human bladder cancer cell line (T24) (transitional cell carcinoma) was purchased from the Food 2.4. Cell Cycle Distribution and Phase Determination. The Industry Research and Development Institute (Hsinchu, cell cycle distribution and sub-G1 phase were analyzed by Evidence-Based Complementary and Alternative Medicine 3 150 150 Cucurbitacin E (24 h) 120 120 G2/M 90 90 G0/G1 G0/G1 Counts Counts 60 G2/M 60 Sub-G1 Sub-G1 30 S 30 S 0 0 0 200 400 600 800 1000 0 200 400 600 800 1000 Control (FL2-A) Cucurbitacin (FL2-A) (a) 100 80 60 40 20 Cell cycle distributionCell cycle (%) 0 Cucurbitacin E 0122448 (1000 nM) Time (h) G0/G1 G2/M S (b) 5 Figure 2: The effects of cucurbitacin E on the G2/M phase arrest in T24 cells. Cells at a density of 2 × 10 cells per well were placed in 12-well plates and then were treated with 1000 nM cucurbitacin E for different time periods (12, 24, or 48 h). Cells were harvested for evaluating the cell cycle distribution as described in the Materials and Methods. (a) The representative of profiles of DNA content; (b) the percentage of cells in G0/G1, S, and G2/M phase in T24 cells. Data revealed a representative experiment in triplicate with similar results. flow cytometry, as described previously [27, 28]. A total of with a ModFit LT program (Verity Software House Inc., 2 × 105 T24 cells/well on 12-well plates were incubated with Topsham, ME, USA).
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