Objective: To study gap junction intercellular communication (GJIC), H-ras oncogene expression and ras oncogene product (P21 ras protein) expression in four human solid tumor cell lines, W1-38, CACO2, A549 and PaCa, and the effects of four compounds, Salvia miltiorrhiza derivative (SMD), d-Limonene, Turmeric derivative I (TD-I) and Turmeric derivative II (TD-II), on them. Methods: The abilities of the four solid tumor cell lines to transfer dye to adjacent cells were examined by the scrape-loading/dye transfer technique, and the H-ras oncogene expression by Northern blotting and P21 ras protein expression by Western blotting. Results: The results showed the loss of intercellular coupling in PaCa cells, slight GJIC in A549 and CACO2 cells, and a good GJIC in W1-38 cells. The four compounds could improve the GJIC of PaCa to different extents. The amount of total and membrane associated P21 ras in PaCa cells were decreased after treatment with SMD, d-Limonene and TD-I (2.5 µg/ml) for 48 h. Concomitantly, the growth of PaCa cells decreased in soft agar and had enhanced GJIC. The relative potency was found to be:d-Limonene>SMD >TD-I=TD-II. There was no significant effect of the four compounds on H-ras oncogene expression. Conclusion: It was suggested that there was an excellent correlation between loss of Lucifer Yellow dye transfer and ras gene mutation rate in the four solid tumor cell lines (ras gene mutation rate inversely correlated with average cell number coupled, r=0.98) i.e., the high ras gene mutation was closely correlated with loss of GJIC in these malignant human tumor cells; The antitumor effect of the monoterpene d-Limonene and the phenol compound, SMD, might be related to inhibition of P21 ras membrane association and enhancement of GJIC, whilst that of the others may be by a different mechanism; The inhibition of P21 ras membrane association was directly related to the enhancement of gap junction intercellular communication.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
gap junction intercellular communication
salvia miltiorrhiza derivative
- TD-I and TD-II:
turmeric derivative I and II
Barbacid M. Ras genes. Annu Rev Biochem 1991; 56:827.
James GL, Galdstein JL. Benzodiazapine peptidomimetics: potent inhibitors of ras farnesylation in animal cells. Science 1993; 260:1937.
Schafer WR, Rine J. Protein prenylation: Genes, enzymes, targets, and functions. Annu Rev Genet 1992; 30:209.
Itoh T, Kaibuchi K, Masuda T, et al. The posttranslational processing of ras P21 is critical for its stimulation of mitogen-activated protein kinase. J Biol Chem 1993; 268:3025.
Dotto GD, El-Fouly MH, Nelson C, et al. Similar and synergistic inhibition of gap junctional communication by ras transformation and tumor promoter treatment of mouse primary keratinocytes. Oncogene 1989; 4:636.
Brissette JL, Kumar NM, Gilula NB, et al. The tumor promoter 12-0-tetradecanoylphorbol-130acetate and the ras oncogene modulate expression and phosphorylation of gap junction proteins. Mol Cell Biol 1991; 11:5364.
Croteau R. Biosynthesis and catabolism of monoterpenes. Chem Rev 1987; 87:929.
Crowell PL, Chang RR, Ren Z, et al. Selective inhibition of isoprenylation of 21–26 kDa proteins by the anticarcinogen d-Limonene and its metabolites. J Biol Chem 1991; 266:17679.
Wattenbery LW, Sparnins VL, Barany G. Inhibition of N-nitrosodiethylamine carcinogenesis in mice by naturally occurring organosulfur compounds and monoterpenes. Cancer Res 1989; 49:2689.
Wattenberg LW, Coccia JB. Inhibition of 4-(methylnitrosoamino)-1-(3-pyridy)-1-butanone carcinogenesis in mice by d-Limonene and citrus fruit oils. Carcinogenesis 1991; 12:115.
Moore CJ, Kennan WS, Wang B, et al. Inhibition of ras-induced rat mammary carcinogenesis by Limonene. Proc Am Assoc Cancer Res 1991; 32:131.
Katiyar SK, Agarwal R, Mukhtar H. Inhibition of tumor promotion in SENCAR mouse skin by ethanol extract of zinginber officinale rhizome. Cancer Res 1996; 56:1023.
Li Y, Fu ZD, Chen XG. Effects of curcumin derivatives on the GJIC of normal and tumor cells. Acta Acad Med Sinicae 1996; 18(2):111.
Chomczynski P, Sacchi N. Single step method of RNA isolation by acid guandidinium thiocyanate-phenochlorform extraction. Anal Biochem 1987; 162:156.
Ruch RJ, Madhukar BV. Reversal of ras-induced inhibition of gap-junctional intercellular communication, transformation, and tumorigenesis by lovastatin. Molecular Carcinogenesis 1993; 7:50.
De Feijter AW, Ray JS, Weghorst CH. Infection of rat liver epithelial cells with v-Ha-ras: correlation between oncogene expression, gap junctional communication, and tumorigenecity. Mol Carinog 1990; 3:54.
Musil LS, Beyer EC, Goodenough DA. Expression of the gap junction connexin 43 in embryomic chick lens: molecular cloning, ultrastructural localization and posttranslational phosphorylation. J Membr Biol 1990; 116:163.
Crow DS, Beyer EC, Paul DL, et al. Phosphorylation of connexin 43 gap junction protein in uninfected and Rous sarcoma virus-transformed mammalian fibroblasts. Mol Cell Biol 1990; 10:1754.
Filson AJ, Azarnia JR, Eyer EC, et al. Tyrosine phosphorylation of a gap junction protein correlated with inhibition of cell-to-cell communication. Cell Growth Differ 1990; 1:661.
Musil LS, Cunningham BA, Edelman GM, et al. Differential phosphorylation of the gap junction protein connexin 43 in junctional communication-competent and deficient cell lines. J Cell Biol 1990; 111:2077.
Lioyd AC, Paterson HF, Morris JDH, et al. P21 H-ras-induced morphological transformation and increased c-myc expression are independent of functional protein kinase C. EMBO J 1989; 8:1099.
Guo HM, Acevedo P, Parsa FD, et al. Gap-junctional protein connexin 43 is expressed in dermis and epidermis of human skin: Differential modulation by retinoids. J Investigative Dermatology 1992; 99:460.
About this article
Cite this article
Chen, X., Taday oshi, H., Yoshihisa, Y. et al. Effects of limonene, salvia miltiorrhiza and turmeric derivatives on H-ras oncogene expression and gap junction intercellular communication in human solid tumor cell lines. Chinese Journal of Cancer Research 10, 162–168 (1998). https://doi.org/10.1007/BF02948353
- Salvia miltiorrhiza derivative (SMD)
- Turmeric derivatives
- H-ras oncogene
- Junction Intercellular Communication (GJIC)