Erk is involved in the differentiation induced by diallyl disulfide in the human gastric cancer cell line MGC803
Cellular & Molecular Biology Letters volume 11, pages 408–423 (2006)
Diallyl disulfide (DADS) is a major constituent of garlic. Previously, we found that DADS both inhibited proliferation in human gastric cancer cells in vitro and in vivo, and induced G2/M arrest. In this study, we investigated whether this differentiation effect was induced by DADS in human gastric cancer MGC803 cells, and whether it was related to an alteration in ERK activity. The results showed that the growth of MGC803 cells was inhibited by DADS. Cells treated with DADS displayed a lower nucleocytoplasmic ratio and tended to form gland and intercellular conjunction structures. The ConA-mediated cell agglutination ratio and cells’ ALP specific activity decreased. In MGC803 cells, dye transfer was limited to a few cells neighbouring the dye-injected cell and to a depth of 1–2 layers beneath the scrape site. However, after treatment with DADS, the LY (Lucifer Yellow) was transferred to several cells immediately neighbouring the microinjected cell and to a depth of 2–4 cell layers from the scrape site. This indicated that DADS induced differentiation in MGC803 cells. Western blot analysis revealed that although DADS did not influence the quantity of ERK1/2 protein expressed, it did decrease its phosphorylation in a concentration-dependent manner, compared with the controls. At 30 mg·L−1, DADS inhibited the activation of ERK1/2 in 15–30 min. These results suggested that the DADS-induced differentiation of MGC803 cells involved an alteration of the ERK1/2 signaling pathway.
extracellular signal-regulated kinase
gap junctional intercellular communication
mitogen-activated protein kinase
phosphate buffered saline
scrape-loading and dye transfer
Fan, P. Eight kinds of cancer hold over 80% of the death rate of all cancer in China. Shu Ju 4 (2005) 6.
You, W.C., Blot, W.J., Chang, Y.S., Ershow, A., Yang, Z.T., An, Q., Henderson, B.E., Fraumeni, J.F. Jr and Wang, T.G. Allium vegetables and reduced risk of stomach cancer. J. Natl. Cancer Inst. 81 (1989) 162–164.
Agarwal, K.C. Therapeutic actions of garlic constituents. Med. Res. Rev. 16 (1996) 111–124.
Sundaram, S.G. and Milner, J.A. Diallyl disulfide induces apoptosis of human colon tumor cells. Carcinogenesis 17 (1996) 669–763.
Sundaram, S.G. and Milner, J.A. Diallyl disulfide suppresses the growth of human colon tumor cell xenografts in athymic nude mice. J. Nutr. 126 (1996) 1355–1361.
Singh, S.V., Mohan, R.R., Agarwal, R., Benson, P.J., Hu, X., Rudy, M.A., Xia, H., Katoh, A., Srivastava, S.K., Mukhtar, H., Gupta, V. and Zaren, H.A. Novel anti-carcinogenic activity of an organosulfide from garlic: inhibition of H-RAS oncogene transformed tumor growth in vivo by diallyl disulfide is associated with inhibition of p21H-ras processing. Biochem. Biophys. Res. Commun. 225 (1996) 660–665.
Knowles, L.M. and Milner, J.A. Possible mechanism by which allyl sulfides suppress neoplastic cell proliferation. J. Nutr. 131 (2001) 1061S–1066S.
Robert, V., Mouille, B., Mayeur, C., Michaud, M. and Blachier, F. Effects of the garlic compound diallyl disulfide on the metabolism, adherence and cell cycle of HT-29 colon carcinoma cell: evidence of sensitive and resistant subpopulations. Carcinogenesis 22 (2001) 1155–1161.
Nakagawa, H., Tsuta, K., Kiuchi, K., Senzaki, H., Tanaka, K., Hioki, K. and Tsubura, A. Growth inhibitory effects of diallyl disulfide on human breast cancer cell lines. Carcinogenesis 22 (2001) 891–897.
Hong, Y.S., Ham, Y.A., Choi, J.H. and Kim, J. Effects of allyl sulfur compounds and extract on the expression of Bcl-2,Bax and p53 in non small cell lung cancer cell lines. Exp. Mol. Med. 32 (2000) 127–134.
Kwon, K.B., Yoo, S.J., Ryu, D.G., Yang, J.Y., Rho, H.W., Kim, J.S., Park, J.W., Kim, H.R. and Park, B.H. Induction of apoptosis by diallyl disulfide through activation of caspase-3 in human leukemia HL-60. Biochem. Pharmacol. 63 (2002) 41–47.
Yuan, J.P., Wang, G.H., Ling, H., Su, Q., Yang, Y.H., Song, Y., Tang, R.J., Liu, Y. and Huang, C. Diallyl disulfide-induced G2/M arrest of human gastric cancer MGC803 cells involves activation of p38 MAP kinase pathways. World J. Gastroenterol. 10 (2004) 2731–2734.
Xiang, S.L., Xiao, X.L., Ling, H., Liao, Q.J., Zhou, X.T., Dong, L. and Su, Q. Antitumor Effect of Diallyl Disulfide on Human Gastric Cancer MGC803 Cells Xenograft in Nude Mice. Ai Zheng 24 (2005) 940–944.
Lewis, T.S., Shapiro, P.S. and Ahn, N.G. Signal transduction through MAP kinase cascades. Adv. Cancer Res. 74 (1998) 49–60.
Sebolt-Leopold, J.S. Development of anticancer drugs targeting the MAPK kinase pathway. Oncogene 19 (2000) 6594–6599.
Kohno, M. and Pouyssegur, J. Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs. Prog. Cell Cycle Res. 5 (2003) 219–224.
Trosko, J.E., Chang, C.C., Wilson, M.R., Upham, B., Hayashi, T. and Wade, M. Gap junctions and the regulation of cellular functions of stem cells during development and differentiation. Methods 20 (2000) 245–264.
Li, X.G., Xie, J.Y. and Lu, Y.Y. Suppressive action of garlic oil on growth and differentiation of human gastric cancer cell line BGC-823. Huaren Xiaohua Zazhi 6 (1998) 10–12.
Chen, Z.M., Chen, Y.Q. and Zhang, C. The Effects of Enzyme-digested Solution from Mensamaria intercedens (Lampart) on Gastric Cancer Cell MGc80-3 in Culture. J. Xiamen University (Natural Science) 37 (1998) 594–599.
Yang, S.M. DMSO induced differentiation of human gastric adenocarcinoma cell line MGC803. Shi Yan Sheng Wu Xue Bao 27 (1994) 281–287.
Chen, R.C., Su, J.H., Yang, S.M., Li, J., Wang, T.J. and Zhou, H. Effect of isoverbascoside, a phenylpropanoid glycoside antioxidant, on proliferation and differentiation of human gastric cancer cell. Acta. Pharmacol. Sin. 23 (2002) 997–1001.
Lea, M.A. and Randolph, V.M. Induction of histone acetylation in rat liver and hepatoma by organosulfur compounds including diallyl disulfide. Anticancer Res. 21 (2001) 2841–2846.
Druesne, N., Pagniez, A., Mayeur, C., Thomas, M., Cherbuy, C., Duee, P-H., Martel, P. and Chaumontet, C. Diallyl disulfide(DADS) increases histone acetylation and p21waf1/cip1 expression in human colon tumor cell lines. Carcinogenesis 25 (2004) 1227–1236.
Ara, C., Massimi, M. and Devirgiliis Conti, L. Retinoic acid modulates gap junctional intercellular communication in hepatocytes and hepatoma cells. Cell. Mol. Life Sci. 59 (2002) 1758–1765.
Cho, J.H., Cho, S.D., Hu, H., Kim, S.H., Lee, S.K. and Lee, Y.S. The role of ERK1/2 and p38 MAP kinase in the preventive mechanisms of mushroom phellinus linteus against the inhibition of gap junctional communication by hydrogen peroxide. Carcinogenesis 23 (2002) 1163–1169.
Simon, A.M. and Goodenough, D.A. Diverse functions of vertrbrate gap junction. Trends Cell Biol. 8 (1998) 477–483.
Carruba, G., Cocciadiferro, L., Bellavia, V., Rizzo, S., Tsatsanis, C., Spandidos, D., Muti, P., Smith, C., Mehta, P. and Castagnetta, L. Intercellular communication and human hepatocellular carcinoma. Ann. N.Y. Acad. Sci. 1028 (2004) 202–212.
Filomeni, G., Aquilano, K., Rotilio, G. and Ciriolo, M.R. Glutathione-related systems and modulation of extracellular signal-regulated kinases are involved in the resistance of AGS adenocarcinoma gastric cells to diallyl disulfide-induced apoptosis. Cancer Res. 65 (2005) 11735–11742.
Wu, X.J., Kassie, F. and Mersch-Sundermann, V. The role of reactive oxygen species (ROS) production on diallyl disulfide (DADS) induced apoptosis and cell cycle arrest in human A549 lung carcinoma cells. Mutat. Res. 579 (2005) 115–124.
Lu, H.F., Sue, C.C., Yu, C.S., Chen, S.C., Chen, G.W. and Chung, J.G. Diallyl disulfide (DADS) induced apoptosis undergo caspase-3 activity in human bladder cancer T24 cells. Food Chem. Toxicol. 42 (2004) 1543–1552.
Wen, J., Zhang, Y., Chen, X., Shen, L., Li, G.C. and Xu, M. Enhancement of diallyl disulfide-induced apoptosis by inhibitors of MAPKs in human HepG2 hepatoma cells. Biochem. Pharmacol. 68 (2004) 323–331.
Rubinfeld, H. and Seger, R. The ERK cascade: a prototype of MARK signaling. Mol. Biotechnol. 31 (2005) 151–174.
Miranda, M.B., Xu, H., Torchia, J.A. and Johnson, D.E. Cytokine-induced myeloid differentiation is dependent on activation of the MEK/ERK pathway. Leuk. Res. 29 (2005) 1293–1306.
Ghosh, M., Gharami, K., Paul, S. and Das, S. Thyroid hormone-induced morphological differentiation and maturation of astrocytes involves activation of protein kinase A and ERK signalling pathway. Eur. J. Neurosci. 22 (2005) 1609–1617.
Kucukkaya, B., Arslan, D.O. and Kan, B. Role of G proteins and ERK activation in hemin-induced erythroid differentiation of K562 cells. Life Sci. 78 (2006) 1217–1224.
Kim, J., Adam, R.M. and Freeman, M.R. Activation of the Erk mitogen-activated protein kinase pathway stimulates neuroendocrine differentiation in LNCaP cells independently of cell cycle withdrawal and STAT3 phosphorylation. Cancer Res. 62 (2002) 1549–1554.
Eriksson, M. and Leppa, S. Mitogen-activated protein kinases and activator protein 1 are required for proliferation and cardiomyocyte differentiation of P19 embryonal carcinoma cells. J. Biol. Chem. 277 (2002) 15992–16001.
Dorsey, J.F., Cunnick, J.M., Mane, S.M., Wu, J., Dorsey, J.F., Cunnick, J.M., Mane, S.M. and Wu, J. Regulation of the Erk2-Erk1 signaling pathway and megakaryocytic differentiation of Bcr-Abl(+) K562 leukemic cells by Gab2. Blood 997 (2002) 1388–1397.
Wall, N.R., Mohammad, R.M. and Al-katib, A.M. Mitogen-activated protein kinase is required for bryostatin-1-induced differentiation of the human acute lymphoblastic leukemia cell line Reh. Cell Growth Differ. 12 (2001) 641–647.
Li, C., Ahlborn, T.E., Kraemer, F.B. and Liu, J. OncostatinM-induced growth inhibition and morphological changes of MDA-MB231 breast cancer cells are abolished by blocking the MEK/ERK signaling pathway. Breast Cancer Res. Treat. 66 (2001) 111–121.
Steinmetz, R., Wagoner, H.A., Zeng, P., Hammond, J.R., Hannon, T.S., Meyers, J.L. and Pescovitz, O.H. Mechanisms regulating the constitutive activation of the extracellular signal-regulated kinase (ERK) signaling pathway in ovarian cancer and the effect of ribonucleic acid interference for ERK1/2 on cancer cell proliferation. Mol. Endocrinol. 18 (2004) 2570–2582.
Knowles, L.M. and Milner, J.A. Diallyl disulfid induces ERK phosphorylation and alters gene expression profiles in human colon tumor cells. J. Nutr. 133 (2003) 2901–2906.
Lin, Y., Chuang, S. and Yang, J. ERK1/2 achieves sustained activation by stimulating MAPK phosphatase-1 degradation via the ubiquitin-proteasome pathway. J. Biol. Chem. 278 (2003) 21534–21541.
About this article
Cite this article
Ling, H., Zhang, LY., Su, Q. et al. Erk is involved in the differentiation induced by diallyl disulfide in the human gastric cancer cell line MGC803. Cell Mol Biol Lett 11, 408–423 (2006). https://doi.org/10.2478/s11658-006-0034-2