Skip to main content

Deep-sea water inhibits metastatic potential in HT-29 human colorectal adenocarcinomas via MAPK/NF-κB signaling pathway

Abstract

A previous investigation showed that deep-sea water (DSW) can affect the expression of genes that regulate metastasis, including cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2), urokinase plasminogen activator (uPA) and uPA receptor (uPAR), in HT-29 human colorectal adenocarcinomas. In the present study, we investigated the effects of DSW on inducible nitric oxide synthase (iNOS) expression and cell migration and also explored the mechanism of DSW-induced anti-metastatic potential in HT-29 human colorectal adenocarcinomas. Cytokine-induced expression of iNOS, which is highly expressed in colon cancer and enhances cancer growth and metastasis, was decreased in a hardness-dependent manner by DSW. Also, the wound healing assay revealed that DSW inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration in a hardness-dependent manner. DSW also decreased the phosphorylation of various MAPKs, including p38, ERK and JNK, and suppressed the nuclear translocation of NF-κB but not c-Jun. The results suggest that DSW may inhibit cancer cell growth related to iNOS overexpression and PKC-mediated cell migration in HT-29 human colorectal adenocarcinomas and the antimetastatic potential of DSW may be regulated by prevention of NF-κB nuclear translocation via inhibition of p38, ERK and JNK phosphorylation. In conclusion, the present investigation demonstrates that DSW inhibits cancer growth and metastasis via down-regulation of iNOS expression and the MAPK/NF-κB signaling pathway.

This is a preview of subscription content, access via your institution.

References

  1. Shao, W., D. Wang, and J. He (2010) The role of gene expression profiling in early-stage non-small cell lung cancer. J. Thorac. Dis. 2: 89–99.

    CAS  Google Scholar 

  2. Nieves-Alicea, R., N. H. Colburn, A. M. Simeone, and A. M. Tari (2009) Programmed cell death 4 inhibits breast cancer cell invasion by increasing tissue inhibitor of metalloproteinases-2 expression. Breast Cancer Res. Treat. 114: 203–209.

    Article  CAS  Google Scholar 

  3. Babykutty, S., P. Suboj, P. Srinivas, A. S. Nair, K. Chandramohan, and S. Gopala (2012) Insidious role of nitric oxide in migration/invasion of colon cancer cells by upregulating MMP-2/9 via activation of cGMP-PKG-ERK signaling pathways. Clin. Exp. Metastasis 29: 471–492.

    Article  CAS  Google Scholar 

  4. Yagihashi, N., H. Kasajima, S. Sugai, K. Matsumoto, Y. Ebina, T. Morita, T. Murakami, and S. Yagihashi (2000) Increased in situ expression of nitric oxide synthase in human colorectal cancer. Virchows Arch. 436: 109–114.

    Article  CAS  Google Scholar 

  5. Ambs, S., W. G. Merriam, W. P. Bennett, E. Felley-Bosco, M. O. Ogunfusika, S. M. Oser, S. Klein, P. G. Shields, T. R. Billiar, and C. C. Harris (1998) Frequent nitric oxide synthase-2 expression in human colon adenomas: Implication for tumor angiogenesis and colon cancer progression. Cancer Res. 58: 334–341.

    CAS  Google Scholar 

  6. Ye, S., W. Yang, Y. Wang, W. Ou, Q. Ma, C. Yu, J. Ren, G. Zhong, H. Shi, Z. Yuan, X. Su, and W. Zhu (2012) Cationic liposome- mediated nitric oxide synthase gene therapy enhances the antitumor effects of cisplatin in lung cancer. Int. J. Mol. Med. 31: 33–42.

    Google Scholar 

  7. Zhao, X., X. Deng, K. Y. Park, L. Qiu, and L. Pang (2013) Purple bamboo salt has anticancer activity in TCA8113 cells in vitro and preventive effects on buccal mucosa cancer in mice in vivo. Exp. Ther. Med. 5: 549–554.

    Google Scholar 

  8. Duffy, M. J., P. M. McGowan, and W. M. Gallagher (2008) Cancer invasion and metastasis: Changing views. J. Pathol. 214: 283–293.

    Article  CAS  Google Scholar 

  9. Jang, J. Y., Y. K. Jeon, and C. W. Kim (2010) Degradation of HER2/neu by ANT2 shRNA suppresses migration and invasiveness of breast cancer cells. BMC Cancer 10: 391.

    Article  Google Scholar 

  10. Steeg, P. S. (2003) Metastasis suppressors alter the signal transduction of cancer cells. Nat. Rev. Cancer 3: 55–63.

    Article  CAS  Google Scholar 

  11. McMahon, B. and H. C. Kwaan (2008) The plasminogen activator system and cancer. Pathophysiol. Haemost. Thromb. 36: 184–194.

    Article  Google Scholar 

  12. Zong, H., F. Wang, Q. X. Fan, and L. X. Wang (2011) Curcumin inhibits metastatic progression of breast cancer cell through suppression of urokinase-type plasminogen activator by NF-kappa B signaling pathways. Mol. Biol. Rep. 39: 4803–4808.

    Article  Google Scholar 

  13. Kong, D., Y. Li, Z. Wang, S. Banerjee, and F. H. Sarkar (2007) Inhibition of angiogenesis and invasion by 3,3′-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res. 67: 3310–3319.

    Article  CAS  Google Scholar 

  14. Hirashima, Y., H. Kobayashi, M. Suzuki, Y. Tanaka, N. Kanayama, and T. Terao (2003) Transforming growth factorbeta1 produced by ovarian cancer cell line HRA stimulates attachment and invasion through an up-regulation of plasminogen activator inhibitor type-1 in human peritoneal mesothelial cells. J. Biol. Chem. 278: 26793–26802.

    Article  CAS  Google Scholar 

  15. Wang, Y. (2001) The role and regulation of urokinase-type plasminogen activator receptor gene expression in cancer invasion and metastasis. Med. Res. Rev. 21: 146–170.

    Article  Google Scholar 

  16. Suzuki, M., H. Kobayashi, Y. Tanaka, Y. Hirashima, N. Kanayama, Y. Takei, Y. Saga, H. Itoh, and T. Terao (2003) Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cell line by overexpression of bikunin. Int. J. Cancer 104: 289–302.

    Article  CAS  Google Scholar 

  17. Chiou, Y. S., M. L. Tsai, K. Nagabhushanam, Y. J. Wang, C. H. Wu, C. T. Ho, and M. H. Pan (2011) Pterostilbene is more potent than resveratrol in preventing azoxymethane (AOM)-induced colon tumorigenesis via activation of the NF-E2-related factor 2 (Nrf2)-mediated antioxidant signaling pathway. J. Agric. Food Chem. 59: 2725–2733.

    Article  CAS  Google Scholar 

  18. Iiizumi, M., W. Liu, S. K. Pai, E. Furuta, and K. Watabe (2008) Drug development against metastasis-related genes and their pathways: A rationale for cancer therapy. Biochim. Biophys. Acta 1786: 87–104.

    CAS  Google Scholar 

  19. Ha, B. G., E. J. Shin, J. E. Park, and Y. H. Shon (2013) Anti-diabetic effect of balanced deep-sea water and its mode of action in high-fat diet induced diabetic mice. Mar. Drugs 11: 4193–4212.

    Article  Google Scholar 

  20. Lee, K. S., J. S. Shin, Y. S. Kwon, D. S. Moon, and K. S. Nam (2013) Suppression of cancer progression and metastasis in HT- 29 human colorectal adenocarcinomas by deep sea water. Biotechnol. Bioproc. Eng. 18: 194–200.

    Article  CAS  Google Scholar 

  21. Kim, S., S. Y Chun, D. H. Lee, K. S. Lee, and K. S. Nam (2013) Mineral-enriched deep-sea water inhibits the metastatic potential of human breast cancer cell lines. Int. J. Oncol. 43: 1691–1700.

    CAS  Google Scholar 

  22. Hwang, H. S., H. A Kim, S. H. Lee, and J. W. Yun (2009) Antiobesity and antidiabetic effects of deep sea water on ob/ob mice. Mar. Biotechnol. 11: 531–539.

    Article  CAS  Google Scholar 

  23. Hataguchi, Y., H. Tai, H. Nakajima, and H. Kimata (2005) Drinking deep-sea water restores mineral imbalance in atopic eczema/ dermatitis syndrome. Eur. J. Clin. Nutr. 59: 1093–1096.

    Article  CAS  Google Scholar 

  24. Castiglioni, S. and J. A. Maier (2011) Magnesium and cancer: A dangerous liason. Magnes. Res. 24: 92–100.

    Google Scholar 

  25. Nasulewicz, A., J. Wietrzyk, F. I. Wolf, S. Dzimira, J. Madej, J. A. Maier, Y. Rayssiguier, A. Mazur, and A. Opolski (2004) Magnesium deficiency inhibits primary tumor growth but favors metastasis in mice. Biochim. Biophys. Acta 1739: 26–32.

    Article  CAS  Google Scholar 

  26. Huang, S. S., C. S. Chiu, T. H. Lin, M. M. Lee, C. Y. Lee, S. J. Chang, W. C. Hou, G. J. Huang, and J. S. Deng (2013) Antioxidant and anti-inflammatory activities of aqueous extract of Centipeda minima. J. Ethnopharmacol. 147: 395–405.

    Article  CAS  Google Scholar 

  27. Lai, W. W., S. C. Hsu, F. S. Chueh, Y. Y. Chen, J. S. Yang, J. P. Lin, J. C. Lien, C. H. Tsai, and J. G. Chung (2013) Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF-kappaB and matrix metalloproteinase- 2/-9 signaling pathways. Anticancer Res. 33: 1941–1950.

    CAS  Google Scholar 

  28. Kwak, J. Y., M. K. Han, K. S. Choi, I. H. Park, S. Y. Park, M. H. Sohn, U. H. Kim, J. R. McGregor, W. E. Samlowski, and C. Y. Yim (2000) Cytokines secreted by lymphokine-activated killer cells induce endogenous nitric oxide synthesis and apoptosis in DLD-1 colon cancer cells. Cell Immunol. 203: 84–94.

    Article  CAS  Google Scholar 

  29. Park, S. W., S. G. Lee, S. H. Song, D. S. Heo, B. J. Park, D. W. Lee, K. H. Kim, and M. W. Sung (2003) The effect of nitric oxide on cyclooxygenase-2 (COX-2) overexpression in head and neck cancer cell lines. Int. J. Cancer 107: 729–738.

    Article  CAS  Google Scholar 

  30. Wang, G. Y., B. Ji, X. Wang, and J. H. Gu (2005) Anti-cancer effect of iNOS inhibitor and its correlation with angiogenesis in gastric cancer. World J. Gastroenterol. 11: 3830–3833.

    CAS  Google Scholar 

  31. Sikora, A. G., A. Gelbard, M. A. Davies, D. Sano, S. Ekmekcioglu, J. Kwon, Y. Hailemichael, P. Jayaraman, J. N. Myers, E. A. Grimm, and W. W. Overwijk (2010) Targeted inhibition of inducible nitric oxide synthase inhibits growth of human melanoma in vivo and synergizes with chemotherapy. Clin. Cancer Res. 16: 1834–1844.

    Article  CAS  Google Scholar 

  32. Takaoka, K., S. Hidaka, S. Hashitani, E. Segawa, M. Yamamura, N. Tanaka, Y. Zushi, K. Noguchi, H. Kishimoto, and M. Urade (2013) Effect of a nitric oxide synthase inhibitor and a CXC chemokine receptor-4 antagonist on tumor growth and metastasis in a xenotransplanted mouse model of adenoid cystic carcinoma of the oral floor. Int. J. Oncol. 43: 737–745.

    CAS  Google Scholar 

  33. Rao, C. V. (2004) Nitric oxide signaling in colon cancer chemoprevention. Mutat. Res. 555: 107–119.

    Article  CAS  Google Scholar 

  34. Zhu, J., C. Luo, P. Wang, Q. He, J. Zhou, and H. Peng (2013) Saikosaponin A mediates the inflammatory response by inhibiting the MAPK and NF-kappaB pathways in LPS-stimulated RAW 264.7 cells. Exp. Ther. Med. 5: 1345–1350.

    CAS  Google Scholar 

  35. Endale, M., S. C. Park, S. Kim, S. H. Kim, Y. Yang, J. Y. Cho, and M. H. Rhee (2013) Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NFkappaB-induced inflammatory mediators production in RAW 264.7 cells. Immunobiol. 218: 1452–1467.

    Article  CAS  Google Scholar 

  36. Yu, H. Y., K. S. Kim, H. I. Moon, K. M. Kim, Y. C. Lee, and J. H. Lee (2012) JNP3, a new compound, suppresses PMA-induced tumor cell invasion via NF-kappaB down regulation in MCF-7 breast cancer cells. Biochem. Biophys. Res. Commun. 421: 190–196.

    Article  CAS  Google Scholar 

  37. Kim, S., J. Han, S. K. Lee, M. Y. Choi, J. Kim, J. Lee, S. P. Jung, J. S. Kim, J. H. Kim, J. H. Choe, J. E. Lee, and S. J. Nam (2012) Berberine suppresses the TPA-induced MMP-1 and MMP-9 expressions through the inhibition of PKC-alpha in breast cancer cells. J. Surg. Res. 176: 21–29.

    Article  Google Scholar 

  38. Hatano, E., B. L. Bennett, A. M. Manning, T. Qian, J. J. Lemastera, and D. A. Brenner (2001) NF-kappaB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNFalpha- and Fas-mediated apoptosis. Gastroenterol. 120: 1251–1262.

    Article  CAS  Google Scholar 

  39. Arias-Salvatierra, D., E. K. Silbergeld, L. C. Acosta-Saavedra, and E. S. Calderon-Aranda (2011) Role of nitric oxide produced by iNOS through NF-?B pathway in migration of cerebellar granule neurons induced by Lipopolysaccharide. Cell Signal 23: 425–435.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kyung-Soo Nam.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lee, KS., Lee, DH., Kwon, YS. et al. Deep-sea water inhibits metastatic potential in HT-29 human colorectal adenocarcinomas via MAPK/NF-κB signaling pathway. Biotechnol Bioproc E 19, 733–739 (2014). https://doi.org/10.1007/s12257-014-0210-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12257-014-0210-6

Keywords

  • deep sea water (DSW)
  • metastasis
  • inducible nitric oxide synthase (iNOS)
  • colon cancer
  • mitogen-activated protein kinase (MAPK)