Effects of okadaic acid on cell growth, anchorage-independent growth, and co-cultures of normal (KMS-6), immortalized (KMST-6), and neoplastically transformed (KMST-6T and KMST-6/RAS) human fibroblasts

  • Israt Jahan
  • Mikio Iijima
  • Tadashi Kondo
  • Masayoshi Namba
Original Paper Experimental Oncology


The effects of okadaic acid (OA) on normal human (KMS-6), its immortalized (KMST-6) and neoplastically transformed (KMST-6T and KMST-6/RAS) cells were investigated as a model of two-stage carcinogenesis. The presence of OA inhibited cell growth of the normal and immortalized cells but not that of the neoplastic KMST-6T cells. In contrast, cell growth of the other neoplastic KMST-6/RAS cells transformed with the Ha-ras oncogene was inhibited by OA. OA enhanced colony formation of KMST-6T cells in soft agar, but it suppressed that of KMST-6/RAS cells. Co-cultures of KMST-6T cells with normal KMS-6 cells showed an increase in focus formation of KMST-6T cells in the presence of OA, whereas focus formation of KMST-6/RAS cells decreased. These results indicate that OA has growth-promoting effects on certain types of transformed human cells.

Key words

Tumor promoter Okadaic acid Human transformed cells Anchorage-independent growth Cell communication 



okadaic acid


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  1. Afshari CA, Kodama S, Bivins HM, Willard TB, Fujiki H, Barrett JC (1993) Induction of neoplastic progression in Syrian hamster embryo cells treated with protein phosphatase inhibitors. Cancer Res 53:1777–1782Google Scholar
  2. Berenblum I (1941) The carcinogenic action of croton resin. Cancer Res 1:44–48Google Scholar
  3. Bialojan C, Takai A (1988) Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Biochem J 256:283–290Google Scholar
  4. Bignami M, Rosa S, Falcone G, Tato F, Katoh F, Yamasaki H (1988) Specific viral oncogenes cause differential effects on cell-to-cell communication relevant to the suppression of the transformed phenotype by normal cells. Mol Carcinog 1:67–75Google Scholar
  5. Enomoto T, Martel N, Kanno Y, Yamasaki H (1984) Inhibition of cell communication between BALB/c 3T3 cells by tumor promoters and protection by cAMP. J Cell Physiol 121:323–333Google Scholar
  6. Gupta RW, Joseph CK, Foster DA (1993) V-Src-induced transformation is inhibited by okadaic acid. Biochem Biophys Res Commun 196:320–327Google Scholar
  7. Hennings H, Lowry DT, Robinson VA, Morgan DL, Fujiki H, Yuspa SH (1992) Activity of diverse tumor promoters in a keratinocyte co-culture model of initiated epidermis. Carcinogenesis 13:2145–2151Google Scholar
  8. Herschman HR, Brankow DW (1987) Colony size, cell density and nature of the tumor promoter are critical variables in expression of a transformed phenotype (focus formation) in co-cultures of UV-TDTx and C3H10T1/2 cells. Carcinogenesis 8:993–998Google Scholar
  9. Jahan I, Mihara K, Bai L, Namba M (1993) Neoplastic transformation and characterization of human fibroblasts by treatment with60Co gamma rays and the human c-Ha-ras oncogene. In Vitro Cell Dev Biol 29:763–767Google Scholar
  10. Katoh F, Fitzgerald DJ, Giroldi L, Fujiki H, Sugimura T, Yamasaki H (1990) Okadaic acid and phorbol esters: comparative effects of these tumor promoters on cell transformation, intercellular communication and differentiation in vitro. Jpn J Cancer Res 81:590–597Google Scholar
  11. Mihara K, Bai L, Kano Y, Miyazaki M, Namba M (1992) Malignant transformation of human fibroblasts previously immortalized with60Co gamma rays. Int J Cancer 50:639–643Google Scholar
  12. Mordan LJ, Dean NM, Honkanen RE, Boynton AL (1990) Okadaic acid: a reversible inhibitor of neoplastic transformation of mouse fibroblasts. Cancer Commun 2:237–241Google Scholar
  13. Namba M, Nishitani K, Fukushima F, Kimoto T (1988) Multistep neoplastic transformation of normal human fibroblasts by Co-60 gamma rays and Ha-ras oncogenes. Mutat Res 199:415–423Google Scholar
  14. Sakai A, Fujiki H (1991) Promotion of BALB/3T3 cell transformation by the okadaic acid class of tumor promoters, okadaic acid and dinophysistoxin-1. Jpn J Cancer Res 82:518–523Google Scholar
  15. Sakai R, Ikeda I, Kitani H, Fujiki H, Takaku F, Rapp U, Sugimu T, Nagao M (1989) Flat reversion by okadaic acid of raf and ret-II transformants. Proc Natl Acad Sci USA 86:9946–9950Google Scholar
  16. Sivak A, Van Duuren BL (1967) Phenotypic expression of transformation: induction in cell culture by a phorbol ester. Science 157:1443–1444Google Scholar
  17. Suganuma M, Fujiki H, Suguri H, Yoshizawa S, Hirota M, Nakayasu M, Ojika M, Wakamatsu K, Yamada K, Sugimura T (1988) Okadaic acid: an additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter. Proc Natl Acad Sci USA 85:1768–1771Google Scholar
  18. Suganuma M, Tatematsu M, Yatsunami J, Yoshizawa S, Okabe S, Uemura D, Fujiki H (1992) An alternative theory of tissue specificity by tumor promotion of okadaic acid in glandular stomach of SD rats. Carcinogenesis 13:1841–1845Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Israt Jahan
    • 1
  • Mikio Iijima
    • 1
  • Tadashi Kondo
    • 1
  • Masayoshi Namba
    • 1
  1. 1.Department of Cell Biology, Institute of Cellular and Molecular BiologyOkayama University Medical SchoolOkayamaJapan

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