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γ-Tocotrienol-induced apoptosis in human gastric cancer SGC-7901 cells is associated with a suppression in mitogen-activated protein kinase signalling

  • Wenguang Sun (a1), Qi Wang (a1), Bingqing Chen (a1), Jiaren Liu (a1) (a2), Huikun Liu (a1) and Weili Xu (a1)...

Tocotrienols have been shown to inhibit proliferation and induce apoptosis in cancer cells. However, the molecular mechanisms involved in tocotrienol-induced apoptosis are still unclear. In the present study, γ-tocotrienol induced apoptosis in human gastric adenocarcinoma SGC-7901 cell line through down regulation of the extracellular signal-regulated kinase (ERK) signalling pathway. Furthermore, γ-tocotrienol-induced apoptosis was accompanied by down regulation of Bcl-2, up regulation of Bax, activation of caspase-3, and subsequent poly (ADP-ribose) polymerase cleavage. These results indicated that up or down regulation of Bcl-2 family proteins play a major role in the initiation of γ-tocotrienol-induced apoptosis as an activator of caspase-3.γ-Tocotrienol also down regulated the activation of the Raf-ERK signalling pathway, and down regulated c-Myc by decreasing the expressions of Raf-1 and p-ERK1/2 proteins. The results suggest that key regulators in tocotrienol-induced apoptosis may be Bcl-2 families and caspase-3 in SGC-7901 cells through down regulation of the Raf-ERK signalling pathway.

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      γ-Tocotrienol-induced apoptosis in human gastric cancer SGC-7901 cells is associated with a suppression in mitogen-activated protein kinase signalling
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Corresponding author
*Corresponding author: Professor Bingqing Chen, fax +86 451 8750 2885, email
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1International Agency for Research on Cancer (2004) Globocan 2002: Cancer Incidence, Mortality and Prevalence Worldwide, version 2.0. IARC CancerBase no. 5 [Ferlay, J, Bray, F, Pisani, P and Parkin, DM, editors]. Lyon, France: IARC Press.
2Yang, L, Parkin, DM, Ferlay, J, Li, L & Chen, Y (2005) Estimates of cancer incidence in China for 2000 and projections for 2005. Cancer Epidemiol Biomarkers Prev 14, 243250.
3Sporn, MB & Suh, N (2002) Chemoprevention: an essential approach to controlling cancer. Nat Rev Cancer 2, 537543.
4Shukla, S & Gupta, S (2005) Dietary agents in the chemoprevention of prostate cancer. Nutr Cancer 53, 1832.
5Packer, L & Landvik, S (1989) Vitamin E: introduction to biochemistry and health benefits. Ann N Y Acad Sci 570, 16.
6Weber, C, Podda, M, Rallis, M, Thiele, JJ, Traber, MG & Packer, L (1997) Efficacy of topically applied tocopherols and tocotrienols in protection of murine skin from oxidative damage induced by UV-irradiation. Free Radic Biol Med 22, 761769.
7He, L, Mo, H, Hadisusilo, S, Qureshi, AA & Elson, CE (1997) Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. J Nutr 127, 668674.
8Nesaretnam, K, Guthrie, N, Chambers, AF & Carroll, KK (1995) Effect of tocotrienols on the growth of a human breast cancer cell line in culture. Lipids 30, 11391143.
9Qureshi, AA, Sami, SA, Salser, WA & Khan, FA (2002) Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans. Atherosclerosis 161, 199207.
10Khanna, S, Roy, S, Ryu, H, Bahadduri, P, Swaan, PW, Ratan, RR & Sen, CK (2003) Molecular basis of vitamin E action: tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration. J Biol Chem 278, 4350843515.
11Nesaretnam, K, Ambra, R, Selvaduray, KR, Radhakrishnan, A, Canali, R & Virgili, F (2004) Tocotrienol-rich fraction from palm oil and gene expression in human breast cancer cells. Ann N Y Acad Sci 1031, 143157.
12Noguchi, N, Hanyu, R, Nonaka, A, Okimoto, Y & Kodama, T (2003) Inhibition of THP-1 cell adhesion to endothelial cells by α-tocopherol and α-tocotrienol is dependent on intracellular concentration of the antioxidants. Free Radic Biol Med 34, 16141620.
13Naito, Y, Shimozawa, M, Kuroda, M, et al. (2005) Tocotrienols reduce 25-hydroxycholesterol-induced monocyte-endothelial cell interaction by inhibiting the surface expression of adhesion molecules. Atherosclerosis 180, 1925.
14McIntyre, BS, Briski, KP, Gapor, A & Sylvester, PW (2000) Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. Proc Soc Exp Biol Med 224, 292301.
15Gysin, R, Azzi, A & Visarius, T (2002) γ-Tocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins. FASEB J 16, 19521954.
16Shah, S, Gapor, A & Sylvester, PW (2003) Role of caspase-8 activation in mediating vitamin E-induced apoptosis in murine mammary cancer cells. Nutr Cancer 45, 236246.
17Shun, MC, Yu, W, Gapor, A, Parsons, R, Atkinson, J, Sanders, BG & Kline, K (2004) Pro-apoptotic mechanisms of action of a novel vitamin E analog (α-TEA) and a naturally occurring form of vitamin E (δ-tocotrienol) in MDA-MB-435 human breast cancer cells. Nutr Cancer 48, 95105.
18Shah, SJ & Sylvester, PW (2005) γ-Tocotrienol inhibits neoplastic mammary epithelial cell proliferation by decreasing Akt and nuclear factor κB activity. Exp Biol Med (Maywood) 230, 235241.
19Agarwal, MK, Agarwal, ML, Athar, M & Gupta, S (2004) Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association. Cell Cycle 3, 205211.
20Janmejai, KS & Sanjay, G (2006) Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells. Biochem Biophys Res Comm 346, 447453.
21Sakai, M, Okabe, M, Tachibana, H & Yamada, K (2006) Apoptosis induction by γ-tocotrienol in human hepatoma Hep3B cells. J Nutr Biochem 17, 672676.
22Salvesen, GS & Dixit, VM (1997) Caspases: intracellular signaling by proteolysis. Cell 91, 443446.
23Seger, R & Krebs, EG (1995) The MAPK signaling cascade. FASEB J 9, 726735.
24Liang, B, Wang, S, Zhu, XG, Yu, YX, Cui, ZR & Yu, YZ (2005) Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer. World J Gastroenterol 11, 623628.
25Kasid, U & Dritschilo, A (2003) RAF antisense oligonucleotide as a tumor radiosensitizer. Oncogene 22, 58765884.
26Marampon, F, Ciccarelli, C & Zani, BM (2006) Down-regulation of c-Myc following MEK/ERK inhibition halts the expression of malignant phenotype in rhabdomyosarcoma and in non muscle-derived human tumors. Mol Cancer 5, 3148.
27Block, G, Patterson, B & Subar, A (1992) Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 18, 129.
28Shao, ZM, Wu, J, Shen, ZZ & Barsky, SH (1998) Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res 58, 48514857.
29Zhou, JR, Mukherjee, P, Gugger, ET, Tanaka, T, Blackburn, GL & Clinton, SK (1998) Inhibition of murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle, apoptosis, and angiogenesis. Cancer Res 58, 52315238.
30Yap, SP, Yuen, KH & Wong, JW (2001) Pharmacokinetics and bioavailability of α-, γ- and δ-tocotrienols under different food status. J Pharm Pharmacol 53, 6771.
31Sylvester, PW, Shah, SJ & Samant, GV (2005) Intracellular signaling mechanisms mediating the antiproliferative and apoptotic effects of γ-tocotrienol in neoplastic mammary epithelial cells. J Plant Physiol 162, 803810.
32Tsujimoto, Y & Shimizu, S (2000) Bcl-2 family: life-or-death switch. FEBS Lett 466, 610.
33Shimizu, S, Narita, M & Tsujimoto, Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399, 483487.
34Sylvester, PW, Nachnani, A, Shah, S & Briski, KP (2002) Role of GTP-binding proteins in reversing the antiproliferative effects of tocotrienols in preneoplastic mammary epithelial cells. Asia Pac J Clin Nutr 11, Suppl. 7, S452S459.
35Wada, T & Penninger, JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23, 28382849.
36Gysin, S, Lee, SH, Dean, NM & McMahon, M (2005) Pharmacologic inhibition of RAF-MEK-ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res 65, 48704880.
37Klein, PJ, Schmidt, CM, Wiesenauer, CA, et al. (2006) The effects of a novel MEK inhibitor PD184161 on MEK-ERK signaling and growth in human liver cancer. Neoplasia 8, 18.
38Chen, BQ, Xue, YB, Liu, JR, Yang, YM, Zheng, YM, Wang, XL & Liu, RH (2003) Inhibition of conjugated linoleic acid on mouse forestomach neoplasia induced by benzo(a)pyrene and chemopreventive mechanisms. World J Gastroenterol 9, 4449.
39Liu, JR, Yang, BF, Chen, BQ, Yang, YM, Dong, HW & Song, YQ (2004) Inhibition of β-ionone on SGC-7901 cell proliferation and upregulation of metalloproteinases-1 and -2 expression. World J Gastroenterol 10, 167171.
40Liu, JR, Chen, BQ, Yang, BF, Dong, HW, Sun, CH, Wang, Q, Guo, S & Song, YQ (2004) Apoptosis of human gastric adenocarcinoma cells induced by β-ionone. World J Gastroenterol 10, 348351.
41Bocca, C, Bozzo, F, Gabriel, L & Miglietta, A (2007) Conjugated linoleic acid inhibits Caco-2 cell growth via ERK-MAPK signaling pathway. J Nutr Biochem 18, 332340.
42Davis, RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103, 239252.
43Chang, L & Karin, M (2001) Mammalian MAP kinase signalling cascades. Nature 410, 3740.
44Johnson, GL & Lapadat, R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 19111912.
45Sarkar, D, Su, ZZ, Lebedeva, S IV, auane, M, Gopalkrishnan, RV, Valerie, K, Dent, P & Fisher, PB (2002) mda-7 (IL-24) Mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK. Proc Natl Acad Sci U S A 99, 1005410059.
46Porras, A, Zuluaga, S, Black, E, Valladares, A, Alvarez, AM, Ambrosino, C, Benito, M & Nebreda, AR (2004) p38 α Mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli. Mol Biol Cell 15, 922933.
47Park, JM, Greten, FR, Li, ZW & Karin, M (2002) Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297, 20482051.
48Juretic, N, Santibanez, JF, Hurtado, C & Martinez, J (2001) ERK 1,2 and p38 pathways are involved in the proliferative stimuli mediated by urokinase in osteoblastic SaOS-2 cell line. J Cell Biochem 83, 9298.
49Yosimichi, G, Nakanishi, T, Nishida, T, Hattori, T, TakanoYamamoto, T & Takigawa, M (2001) CTGF/Hcs24 induces chondrocyte differentiation through a p38 mitogen-activated protein kinase (p38MAPK), and proliferation through a p44/42 MAPK/extracellular-signal regulated kinase (ERK). Eur J Biochem 268, 60586065.
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