Skip to main content
  • Published:

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

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.

Abbreviations

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 4 (2005) 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 and Wang, T.G. Allium vegetables and reduced risk of stomach cancer. J. Natl. Cancer Inst. 81 (1989) 162–164.

    PubMed  CAS  Google Scholar 

  3. Agarwal, K.C. Therapeutic actions of garlic constituents. Med. Res. Rev. 16 (1996) 111–124.

    Article  PubMed  CAS  Google Scholar 

  4. Sundaram, S.G. and Milner, J.A. Diallyl disulfide induces apoptosis of human colon tumor cells. Carcinogenesis 17 (1996) 669–763.

    PubMed  CAS  Google Scholar 

  5. 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.

    PubMed  CAS  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. 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.

    Article  PubMed  CAS  Google Scholar 

  7. Knowles, L.M. and Milner, J.A. Possible mechanism by which allyl sulfides suppress neoplastic cell proliferation. J. Nutr. 131 (2001) 1061S–1066S.

    PubMed  CAS  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. 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.

    Article  PubMed  CAS  Google Scholar 

  10. 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.

    PubMed  CAS  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. 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.

    Article  PubMed  CAS  Google Scholar 

  12. 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.

    PubMed  CAS  Google Scholar 

  13. 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.

    PubMed  CAS  Google Scholar 

  14. Lewis, T.S., Shapiro, P.S. and Ahn, N.G. Signal transduction through MAP kinase cascades. Adv. Cancer Res. 74 (1998) 49–60.

    Article  PubMed  CAS  Google Scholar 

  15. Sebolt-Leopold, J.S. Development of anticancer drugs targeting the MAPK kinase pathway. Oncogene 19 (2000) 6594–6599.

    Article  PubMed  CAS  Google Scholar 

  16. Kohno, M. and Pouyssegur, J. Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs. Prog. Cell Cycle Res. 5 (2003) 219–224.

    PubMed  Google Scholar 

  17. 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.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    Google Scholar 

  19. 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.

    Google Scholar 

  20. Yang, S.M. DMSO induced differentiation of human gastric adenocarcinoma cell line MGC803. Shi Yan Sheng Wu Xue Bao 27 (1994) 281–287.

    PubMed  CAS  Google Scholar 

  21. 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.

    PubMed  CAS  Google Scholar 

  22. 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.

    PubMed  CAS  Google Scholar 

  23. 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.

    Article  PubMed  CAS  Google Scholar 

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. 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.

    Article  PubMed  CAS  Google Scholar 

  26. Simon, A.M. and Goodenough, D.A. Diverse functions of vertrbrate gap junction. Trends Cell Biol. 8 (1998) 477–483.

    Article  PubMed  CAS  Google Scholar 

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. 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.

    Article  PubMed  CAS  Google Scholar 

  29. 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.

    PubMed  CAS  Google Scholar 

  30. 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.

    Article  PubMed  CAS  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. Rubinfeld, H. and Seger, R. The ERK cascade: a prototype of MARK signaling. Mol. Biotechnol. 31 (2005) 151–174.

    Article  PubMed  CAS  Google Scholar 

  33. 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.

    Article  PubMed  CAS  Google Scholar 

  34. 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.

    Article  PubMed  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. 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.

    PubMed  CAS  Google Scholar 

  37. 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.

    Article  PubMed  CAS  Google Scholar 

  38. 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.

    Article  Google Scholar 

  39. 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.

    PubMed  CAS  Google Scholar 

  40. 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.

    Article  PubMed  CAS  Google Scholar 

  41. 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.

    Article  PubMed  CAS  Google Scholar 

  42. 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.

    PubMed  CAS  Google Scholar 

  43. 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Qi Su.

Rights and permissions

Reprints and permissions

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11658-006-0034-2

Key words