Skip to main content
PMC home page
Cellular & Molecular Biology Letters logoLink to Cellular & Molecular Biology Letters
. 2006 Sep 1;11(3):408–423. doi: 10.2478/s11658-006-0034-2

Erk is involved in the differentiation induced by diallyl disulfide in the human gastric cancer cell line MGC803

Hui Ling 1, Liang-Yun Zhang 1, Qi Su 1,✉, Ying Song 1, Zhao-Yang Luo 1, Xiu Tian Zhou 1, Xi Zeng 1, Jie He 1, Hui Tan 1, Jing-Ping Yuan 1
PMCID: PMC6472800  PMID: 16874458

Abstract

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.

Key words: Diallyl disulfide, Stomach neoplasm, Differentiation, ERK

Full Text

The Full Text of this article is available as a PDF (863.6 KB).

Abbreviations used

ALP

alkaline phosphatase

ConA

concanavalin A

DADS

diallyl disulfide

DAS

diallyl sulfide

ERK

extracellular signal-regulated kinase

GJIC

gap junctional intercellular communication

LY

Lucifer Yellow

MAPK

mitogen-activated protein kinase

MTT

tihiazolyl blue

PBS

phosphate buffered saline

RA

retinoic acid

SLDT

scrape-loading and dye transfer

References

  • 1.Fan P. Eight kinds of cancer hold over 80% of the death rate of all cancer in China. Shu Ju. 2005;4:6. [Google Scholar]
  • 2.You W.C., Blot W.J., Chang Y.S., Ershow A., Yang Z.T., An Q., Henderson B.E., Fraumeni J.F., Jr, Wang T.G. Allium vegetables and reduced risk of stomach cancer. J. Natl. Cancer Inst. 1989;81:162–164. doi: 10.1093/jnci/81.2.162. [DOI] [PubMed] [Google Scholar]
  • 3.Agarwal K.C. Therapeutic actions of garlic constituents. Med. Res. Rev. 1996;16:111–124. doi: 10.1002/(SICI)1098-1128(199601)16:1<111::AID-MED4>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]
  • 4.Sundaram S.G., Milner J.A. Diallyl disulfide induces apoptosis of human colon tumor cells. Carcinogenesis. 1996;17:669–763. doi: 10.1093/carcin/17.4.669. [DOI] [PubMed] [Google Scholar]
  • 5.Sundaram S.G., Milner J.A. Diallyl disulfide suppresses the growth of human colon tumor cell xenografts in athymic nude mice. J. Nutr. 1996;126:1355–1361. doi: 10.1093/jn/126.5.1355. [DOI] [PubMed] [Google Scholar]
  • 6.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., 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. 1996;225:660–665. doi: 10.1006/bbrc.1996.1226. [DOI] [PubMed] [Google Scholar]
  • 7.Knowles L.M., Milner J.A. Possible mechanism by which allyl sulfides suppress neoplastic cell proliferation. J. Nutr. 2001;131:1061S–1066S. doi: 10.1093/jn/131.3.1061S. [DOI] [PubMed] [Google Scholar]
  • 8.Robert V., Mouille B., Mayeur C., Michaud M., 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. 2001;22:1155–1161. doi: 10.1093/carcin/22.8.1155. [DOI] [PubMed] [Google Scholar]
  • 9.Nakagawa H., Tsuta K., Kiuchi K., Senzaki H., Tanaka K., Hioki K., Tsubura A. Growth inhibitory effects of diallyl disulfide on human breast cancer cell lines. Carcinogenesis. 2001;22:891–897. doi: 10.1093/carcin/22.6.891. [DOI] [PubMed] [Google Scholar]
  • 10.Hong Y.S., Ham Y.A., Choi J.H., 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. 2000;32:127–134. doi: 10.1038/emm.2000.22. [DOI] [PubMed] [Google Scholar]
  • 11.Kwon K.B., Yoo S.J., Ryu D.G., Yang J.Y., Rho H.W., Kim J.S., Park J.W., Kim H.R., Park B.H. Induction of apoptosis by diallyl disulfide through activation of caspase-3 in human leukemia HL-60. Biochem. Pharmacol. 2002;63:41–47. doi: 10.1016/S0006-2952(01)00860-7. [DOI] [PubMed] [Google Scholar]
  • 12.Yuan J.P., Wang G.H., Ling H., Su Q., Yang Y.H., Song Y., Tang R.J., Liu Y., Huang C. Diallyl disulfide-induced G2/M arrest of human gastric cancer MGC803 cells involves activation of p38 MAP kinase pathways. World J. Gastroenterol. 2004;10:2731–2734. doi: 10.3748/wjg.v10.i18.2731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Xiang S.L., Xiao X.L., Ling H., Liao Q.J., Zhou X.T., Dong L., Su Q. Antitumor Effect of Diallyl Disulfide on Human Gastric Cancer MGC803 Cells Xenograft in Nude Mice. Ai Zheng. 2005;24:940–944. [PubMed] [Google Scholar]
  • 14.Lewis T.S., Shapiro P.S., Ahn N.G. Signal transduction through MAP kinase cascades. Adv. Cancer Res. 1998;74:49–60. doi: 10.1016/S0065-230X(08)60765-4. [DOI] [PubMed] [Google Scholar]
  • 15.Sebolt-Leopold J.S. Development of anticancer drugs targeting the MAPK kinase pathway. Oncogene. 2000;19:6594–6599. doi: 10.1038/sj.onc.1204083. [DOI] [PubMed] [Google Scholar]
  • 16.Kohno M., Pouyssegur J. Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs. Prog. Cell Cycle Res. 2003;5:219–224. [PubMed] [Google Scholar]
  • 17.Trosko J.E., Chang C.C., Wilson M.R., Upham B., Hayashi T., Wade M. Gap junctions and the regulation of cellular functions of stem cells during development and differentiation. Methods. 2000;20:245–264. doi: 10.1006/meth.1999.0941. [DOI] [PubMed] [Google Scholar]
  • 18.Li X.G., Xie J.Y., Lu Y.Y. Suppressive action of garlic oil on growth and differentiation of human gastric cancer cell line BGC-823. Huaren Xiaohua Zazhi. 1998;6:10–12. [Google Scholar]
  • 19.Chen Z.M., Chen Y.Q., 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) 1998;37:594–599. [Google Scholar]
  • 20.Yang S.M. DMSO induced differentiation of human gastric adenocarcinoma cell line MGC803. Shi Yan Sheng Wu Xue Bao. 1994;27:281–287. [PubMed] [Google Scholar]
  • 21.Chen R.C., Su J.H., Yang S.M., Li J., Wang T.J., Zhou H. Effect of isoverbascoside, a phenylpropanoid glycoside antioxidant, on proliferation and differentiation of human gastric cancer cell. Acta. Pharmacol. Sin. 2002;23:997–1001. [PubMed] [Google Scholar]
  • 22.Lea M.A., Randolph V.M. Induction of histone acetylation in rat liver and hepatoma by organosulfur compounds including diallyl disulfide. Anticancer Res. 2001;21:2841–2846. [PubMed] [Google Scholar]
  • 23.Druesne N., Pagniez A., Mayeur C., Thomas M., Cherbuy C., Duee P.-H., Martel P., Chaumontet C. Diallyl disulfide(DADS) increases histone acetylation and p21waf1/cip1 expression in human colon tumor cell lines. Carcinogenesis. 2004;25:1227–1236. doi: 10.1093/carcin/bgh123. [DOI] [PubMed] [Google Scholar]
  • 24.Ara C., Massimi M., Devirgiliis Conti L. Retinoic acid modulates gap junctional intercellular communication in hepatocytes and hepatoma cells. Cell. Mol. Life Sci. 2002;59:1758–1765. doi: 10.1007/PL00012503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Cho J.H., Cho S.D., Hu H., Kim S.H., Lee S.K., 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. 2002;23:1163–1169. doi: 10.1093/carcin/23.7.1163. [DOI] [PubMed] [Google Scholar]
  • 26.Simon A.M., Goodenough D.A. Diverse functions of vertrbrate gap junction. Trends Cell Biol. 1998;8:477–483. doi: 10.1016/S0962-8924(98)01372-5. [DOI] [PubMed] [Google Scholar]
  • 27.Carruba G., Cocciadiferro L., Bellavia V., Rizzo S., Tsatsanis C., Spandidos D., Muti P., Smith C., Mehta P., Castagnetta L. Intercellular communication and human hepatocellular carcinoma. Ann. N.Y. Acad. Sci. 2004;1028:202–212. doi: 10.1196/annals.1322.025. [DOI] [PubMed] [Google Scholar]
  • 28.Filomeni G., Aquilano K., Rotilio G., 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. 2005;65:11735–11742. doi: 10.1158/0008-5472.CAN-05-3067. [DOI] [PubMed] [Google Scholar]
  • 29.Wu X.J., Kassie F., 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. 2005;579:115–124. doi: 10.1016/j.mrfmmm.2005.02.026. [DOI] [PubMed] [Google Scholar]
  • 30.Lu H.F., Sue C.C., Yu C.S., Chen S.C., Chen G.W., Chung J.G. Diallyl disulfide (DADS) induced apoptosis undergo caspase-3 activity in human bladder cancer T24 cells. Food Chem. Toxicol. 2004;42:1543–1552. doi: 10.1016/j.fct.2003.06.001. [DOI] [PubMed] [Google Scholar]
  • 31.Wen J., Zhang Y., Chen X., Shen L., Li G.C., Xu M. Enhancement of diallyl disulfide-induced apoptosis by inhibitors of MAPKs in human HepG2 hepatoma cells. Biochem. Pharmacol. 2004;68:323–331. doi: 10.1016/j.bcp.2004.03.027. [DOI] [PubMed] [Google Scholar]
  • 32.Rubinfeld H., Seger R. The ERK cascade: a prototype of MARK signaling. Mol. Biotechnol. 2005;31:151–174. doi: 10.1385/MB:31:2:151. [DOI] [PubMed] [Google Scholar]
  • 33.Miranda M.B., Xu H., Torchia J.A., Johnson D.E. Cytokine-induced myeloid differentiation is dependent on activation of the MEK/ERK pathway. Leuk. Res. 2005;29:1293–1306. doi: 10.1016/j.leukres.2005.03.016. [DOI] [PubMed] [Google Scholar]
  • 34.Ghosh M., Gharami K., Paul S., Das S. Thyroid hormone-induced morphological differentiation and maturation of astrocytes involves activation of protein kinase A and ERK signalling pathway. Eur. J. Neurosci. 2005;22:1609–1617. doi: 10.1111/j.1460-9568.2005.04351.x. [DOI] [PubMed] [Google Scholar]
  • 35.Kucukkaya B., Arslan D.O., Kan B. Role of G proteins and ERK activation in hemin-induced erythroid differentiation of K562 cells. Life Sci. 2006;78:1217–1224. doi: 10.1016/j.lfs.2005.06.041. [DOI] [PubMed] [Google Scholar]
  • 36.Kim J., Adam R.M., 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. 2002;62:1549–1554. [PubMed] [Google Scholar]
  • 37.Eriksson M., 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. 2002;277:15992–16001. doi: 10.1074/jbc.M107340200. [DOI] [PubMed] [Google Scholar]
  • 38.Dorsey J.F., Cunnick J.M., Mane S.M., Wu J., Dorsey J.F., Cunnick J.M., Mane S.M., Wu J. Regulation of the Erk2-Erk1 signaling pathway and megakaryocytic differentiation of Bcr-Abl(+) K562 leukemic cells by Gab2. Blood. 2002;997:1388–1397. doi: 10.1182/blood.V99.4.1388. [DOI] [PubMed] [Google Scholar]
  • 39.Wall N.R., Mohammad R.M., 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. 2001;12:641–647. [PubMed] [Google Scholar]
  • 40.Li C., Ahlborn T.E., Kraemer F.B., 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. 2001;66:111–121. doi: 10.1023/A:1010614724664. [DOI] [PubMed] [Google Scholar]
  • 41.Steinmetz R., Wagoner H.A., Zeng P., Hammond J.R., Hannon T.S., Meyers J.L., 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. 2004;18:2570–2582. doi: 10.1210/me.2004-0082. [DOI] [PubMed] [Google Scholar]
  • 42.Knowles L.M., Milner J.A. Diallyl disulfid induces ERK phosphorylation and alters gene expression profiles in human colon tumor cells. J. Nutr. 2003;133:2901–2906. doi: 10.1093/jn/133.9.2901. [DOI] [PubMed] [Google Scholar]
  • 43.Lin Y., Chuang S., Yang J. ERK1/2 achieves sustained activation by stimulating MAPK phosphatase-1 degradation via the ubiquitin-proteasome pathway. J. Biol. Chem. 2003;278:21534–21541. doi: 10.1074/jbc.M301854200. [DOI] [PubMed] [Google Scholar]

Articles from Cellular & Molecular Biology Letters are provided here courtesy of BMC

RESOURCES