RRR-α-tocopheryl succinate induces apoptosis in human gastric cancer cells via the NF-κB signaling pathway

Sun,Yanpei; Zhao,Yan; Hou,Liying; Zhang,Xuguang; Zhang,Zhihong; Wu,Kun

doi:10.3892/or.2014.3282

RRR-α-tocopheryl succinate induces apoptosis in human gastric cancer cells via the NF-κB signaling pathway

Authors:
- Yanpei Sun
- Yan Zhao
- Liying Hou
- Xuguang Zhang
- Zhihong Zhang
- Kun Wu
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Affiliations: Department of Nutrition and Food, Harbin Medical University, Harbin, Heilongjiang, P.R. China, Food Processing Institute, Heilongjiang Academy of Agricultural Sciences, Harbin, Heilongjiang, P.R. China
Published online on: June 23, 2014 https://doi.org/10.3892/or.2014.3282
Pages: 1243-1248

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Abstract

To investigate the effects of the nuclear factor (NF)-κB signaling pathway on the induction of apoptosis by vitamin E succinate (RRR-α-tocopheryl succinate; VES) in human gastric carcinoma cells. Human gastric carcinoma SGC-7901 cells were treated with temperate concentrations of VES and pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB. Cell viability and apoptosis were respectively estimated by methylthiazol tetrazolium (MTT) assay and the Annexin V‑FITC method. Western blot analysis was used to evaluate the protein expressions of NF-κBp65 and Bcl-2 family members Bcl-2, Bax and cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase (PARP). The DNA-binding activity of NF-κBp65 was measured by electrophoretic mobility shift assay (EMSA). Reverse transcription and polymerase chain reaction (RT-PCR) was implemented to evaluate the transcription of inhibitor of apoptosis (IAP) genes. Apoptosis assessment showed that VES induces apoptotic cell death in human gastric carcinoma cells. In the following experiments, PDTC (100 µM) was used in cell treatment 2 h before VES. The decreased ratio of the nuclear and cytosolic NF-κBp65 protein level was induced by VES and PDTC reinforced this trend. PDTC treatment significantly enhanced the decrease of NF-κB-DNA binding activity induced by VES in human gastric SGC-7901. The decrease in protein expression of Bcl-2 as well as the increase in the protein expression of Bax were induced by VES treatment. The cleavage of caspase-9, caspase-3 and PARP was induced. There was no effect on the gene transcription of c-IAP-1, c-IAP-2, and x-linked IAP (XIAP) compared with the control group, whereas mRNA levels of survivin and the neuronal apoptosis inhibitory protein (NAIP) markedly decreased. Notably, pretreatment with PDTC reinforced all the above VES-induced effects. In conclusion, VES-induced apoptosis in SGC-7901 cells is accompanied by the inhibition of the NF-κB signaling pathway, including changes in Bcl-2 family members, cleavage of caspases and gene transcription of survivin and NAIP.

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1	Foukakis T, Lundell L, Gubanski M and Lind PA: Advances in the treatment of patients with gastric adenocarcinoma. Acta Oncol. 46:277–285. 2007. View Article : Google Scholar
2	Tomasetti M, Gellert N, Procopio A and Neuzil J: A vitamin E analogue suppresses malignant mesothelioma in a preclinical model: a future drug against a fatal neoplastic disease? Int J Cancer. 109:641–642. 2004. View Article : Google Scholar
3	Neuzil J, Weber T, Gellert N and Weber C: Selective cancer cell killing by alpha-tocopheryl succinate. Br J Cancer. 84:87–89. 2001. View Article : Google Scholar : PubMed/NCBI
4	Malafa MP, Fokum FD, Mowlavi A, Abusief M and King M: Vitamin E inhibits melanoma growth in mice. Surgery. 131:85–91. 2002. View Article : Google Scholar : PubMed/NCBI
5	Kline K, Yu W and Sanders BG: Vitamin E and breast cancer. J Nutr. 134:S3458–S3462. 2004.
6	Wu K, Zhao Y, Liu BH, et al: RRR-alpha-tocopheryl succinate inhibits human gastric cancer SGC-7901 cell growth by inducing apoptosis and DNA synthesis arrest. World J Gastroenterol. 8:26–30. 2002.PubMed/NCBI
7	Dong LF, Jameson VJ, Tilly D, et al: Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex II. J Biol Chem. 286:3717–3728. 2011. View Article : Google Scholar : PubMed/NCBI
8	Wu K, Li Y, Zhao Y, et al: Roles of Fas signaling pathway in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells. World J Gastroenterol. 8:982–986. 2002.PubMed/NCBI
9	Wu K, Zhao Y, Li GC and Yu WP: c-Jun N-terminal kinase is required for vitamin E succinate-induced apoptosis in human gastric cancer cells. World J Gastroenterol. 10:1110–1114. 2004.PubMed/NCBI
10	Huang X, Zhang Z, Jia L, Zhao Y, Zhang X and Wu K: Endoplasmic reticulum stress contributes to vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells. Cancer Lett. 296:123–131. 2010. View Article : Google Scholar : PubMed/NCBI
11	Guo JL, Zheng SJ, Li YN, et al: Toxicarioside A inhibits SGC-7901 proliferation, migration and invasion via NF-κB/bFGF signaling. World J Gastroenterol. 18:1602–1609. 2012.PubMed/NCBI
12	Long YM, Ye S, Rong J and Xie WR: Nuclear factor kappa B: a marker of chemotherapy for human stage IV gastric carcinoma. World J Gastroenterol. 14:4739–4744. 2008. View Article : Google Scholar : PubMed/NCBI
13	Zhu BS, Xing CG, Lin F, Fan XQ, Zhao K and Qin ZH: Blocking NF-kappaB nuclear translocation leads to p53-related autophagy activation and cell apoptosis. World J Gastroenterol. 17:478–487. 2011. View Article : Google Scholar : PubMed/NCBI
14	Li X and Stark GR: NFkappaB-dependent signaling pathways. Exp Hematol. 30:285–296. 2002. View Article : Google Scholar
15	Karin M and Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol. 3:221–227. 2002. View Article : Google Scholar : PubMed/NCBI
16	Gilmore TD: The Re1/NF-kappa B/I kappa B signal transduction pathway and cancer. Cancer Treat Res. 115:241–265. 2003. View Article : Google Scholar : PubMed/NCBI
17	Bharti AC and Aggarwal BB: Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol. 64:883–888. 2002. View Article : Google Scholar : PubMed/NCBI
18	Chen W, Li Z, Bai L and Lin Y: NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target. Front Biosci. 16:1172–1185. 2011. View Article : Google Scholar : PubMed/NCBI
19	Sebens S, Arlt A and Schafer H: NF-kappaB as a molecular target in the therapy of pancreatic carcinoma. Recent Results Cancer Res. 177:151–164. 2008. View Article : Google Scholar : PubMed/NCBI
20	Wu K, Shan YJ, Zhao Y, Yu JW and Liu BH: Inhibitory effects of RRR-alpha-tocopheryl succinate on benzo(a)pyrene (B(a)P)-induced forestomach carcinogenesis in female mice. World J Gastroenterol. 7:60–65. 2001.PubMed/NCBI
21	Zhang X, Peng X, Yu W, et al: Alpha-tocopheryl succinate enhances doxorubicin-induced apoptosis in human gastric cancer cells via promotion of doxorubicin influx and suppression of doxorubicin efflux. Cancer Lett. 307:174–181. 2011. View Article : Google Scholar
22	Huang X, Li L, Zhang L, et al: Crosstalk between endoplasmic reticulum stress and oxidative stress in apoptosis induced by alpha-tocopheryl succinate in human gastric carcinoma cells. Br J Nutr. 109:1–9. 2013. View Article : Google Scholar
23	Chen X, Kandasamy K and Srivastava RK: Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B in tumor necrosis factor-related apoptosis-inducing ligand signaling. Cancer Res. 63:1059–1066. 2003.PubMed/NCBI
24	Sun SC and Xiao G: Deregulation of NF-kappaB and its upstream kinases in cancer. Cancer Metastasis Rev. 22:405–422. 2003. View Article : Google Scholar : PubMed/NCBI
25	Lin A and Karin M: NF-kappaB in cancer: a marked target. Semin Cancer Biol. 13:107–114. 2003. View Article : Google Scholar : PubMed/NCBI
26	Neuzil J, Svensson I, Weber T, Weber C and Brunk UT: alpha-tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilisation. FEBS Lett. 445:295–300. 1999. View Article : Google Scholar
27	Wang XF, Witting PK, Salvatore BA and Neuzil J: Vitamin E analogs trigger apoptosis in HER2/erbB2-overexpressing breast cancer cells by signaling via the mitochondrial pathway. Biochem Biophys Res Commun. 326:282–289. 2005. View Article : Google Scholar : PubMed/NCBI
28	Yu W, Sanders BG and Kline K: RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. Cancer Res. 63:2483–2491. 2003.PubMed/NCBI
29	Crispen PL, Uzzo RG, Golovine K, et al: Vitamin E succinate inhibits NF-kappaB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention. Prostate. 67:582–590. 2007. View Article : Google Scholar : PubMed/NCBI
30	Dalen H and Neuzil J: Alpha-tocopheryl succinate sensitises a T Lymphoma cell line to TRAIL-induced apoptosis by suppressing NF-kappaB activation. Br J Cancer. 88:153–158. 2003. View Article : Google Scholar : PubMed/NCBI
31	Mitsiades N, Mitsiades CS, Richardson PG, et al: The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood. 101:2377–2380. 2003. View Article : Google Scholar
32	Zheng B, Georgakis GV, Li Y, et al: Induction of cell cycle arrest and apoptosis by the proteasome inhibitor PS-341 in Hodgkin disease cell lines is independent of inhibitor of nuclear factor-kappaB mutations or activation of the CD30, CD40, and RANK receptors. Clin Cancer Res. 10:3207–3215. 2004. View Article : Google Scholar : PubMed/NCBI
33	Cilloni D, Messa F, Arruga F, et al: The NF-kappaB pathway blockade by the IKK inhibitor PS1145 can overcome imatinib resistance. Leukemia. 20:61–67. 2006. View Article : Google Scholar : PubMed/NCBI
34	Dai Y, Pei XY, Rahmani M, Conrad DH, Dent P and Grant S: Interruption of the NF-kappaB pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells. Blood. 103:2761–2770. 2004. View Article : Google Scholar : PubMed/NCBI
35	Li H and Lin X: Positive and negative signaling components involved in TNFalpha-induced NF-kappaB activation. Cytokine. 41:1–8. 2008. View Article : Google Scholar : PubMed/NCBI
36	Müerköster S, Arlt A, Sipos B, et al: Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells. Cancer Res. 65:1316–1324. 2005.
37	Viatour P, Bentires-Alj M, Chariot A, et al: NF-kappa B2/p100 induces Bcl-2 expression. Leukemia. 17:1349–1356. 2003. View Article : Google Scholar : PubMed/NCBI
38	Al-Harbi S, Hill BT, Mazumder S, et al: An antiapoptotic BCL-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737. Blood. 118:3579–3590. 2011. View Article : Google Scholar : PubMed/NCBI
39	Kelly PN and Strasser A: The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. 18:1414–1424. 2011. View Article : Google Scholar : PubMed/NCBI
40	Oltvai ZN, Milliman CL and Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 74:609–619. 1993. View Article : Google Scholar : PubMed/NCBI
41	Pop C and Salvesen GS: Human caspases: activation, specificity, and regulation. J Biol Chem. 284:21777–21781. 2009. View Article : Google Scholar : PubMed/NCBI
42	Olsson M and Zhivotovsky B: Caspases and cancer. Cell Death Differ. 18:1441–1449. 2011. View Article : Google Scholar
43	Gross A, McDonnell JM and Korsmeyer SJ: BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13:1899–1911. 1999. View Article : Google Scholar : PubMed/NCBI
44	Gyrd-Hansen M, Darding M, Miasari M, et al: IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis. Nat Cell Biol. 10:1309–1317. 2008. View Article : Google Scholar : PubMed/NCBI
45	Trocoli A and Djavaheri-Mergny M: The complex interplay between autophagy and NF-kappaB signaling pathways in cancer cells. Am J Cancer Res. 1:629–649. 2011.PubMed/NCBI
46	Neuzil J, Tomasetti M, Zhao Y, et al: Vitamin E analogs, a novel group of “mitocans,” as anticancer agents: the importance of being redox-silent. Mol Pharmacol. 71:1185–1199. 2007.