Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 Aug;74(4):613–618. doi: 10.1038/bjc.1996.410

Differential effect of polyunsaturated fatty acids on cell proliferation during human epithelial in vitro carcinogenesis: involvement of epidermal growth factor receptor tyrosine kinase.

S Mollerup 1, A Haugen 1
PMCID: PMC2074662  PMID: 8761379

Abstract

Polyunsaturated fatty acids (PUFAs) have been implicated in tumour development and have been shown to influence cell proliferation in vitro. We report here that n-3 and n-6 PUFAs at concentration > 10 microM inhibited the proliferation of a human kidney epithelial cell line (21HKE), which has retained phenotypic characteristics of normal kidney epithelial cells. In contrast, the proliferation was stimulated by n-3 and n-6 PUFAs at concentrations < 10 microM under defined growth conditions. The stimulatory effect of n-3 and n-6 PUFAs was even more profound in the presence of EGF. In human kidney epithelial cell lines reflecting different stages of transformation (11HKE and 1THKEras), the stimulatory effect was abrogated both in the presence and absence of EGF. Saturated fatty acids did not show any stimulatory effect on cell growth. The tyrosine kinase inhibitors genistein and tyrphostin-47 inhibited EGF-induced protein tyrosine phosphorylation dose-dependently in the 21HKE cells, and abolished the growth stimulatory effect of docosahexaenoic acid (DHA). This indicates the involvement of EGF receptor tyrosine kinase activity in the observed increase in cell proliferation.

Full text

PDF
616

Images in this article

615Figure 2
on p.615

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akiyama T., Ishida J., Nakagawa S., Ogawara H., Watanabe S., Itoh N., Shibuya M., Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987 Apr 25;262(12):5592–5595. [PubMed] [Google Scholar]
  2. Aylsworth C. F., Jone C., Trosko J. E., Meites J., Welsch C. W. Promotion of 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis by high dietary fat in the rat: possible role of intercellular communication. J Natl Cancer Inst. 1984 Mar;72(3):637–645. [PubMed] [Google Scholar]
  3. Bandyopadhyay G. K., Hwang S., Imagawa W., Nandi S. Role of polyunsaturated fatty acids as signal transducers: amplification of signals from growth factor receptors by fatty acids in mammary epithelial cells. Prostaglandins Leukot Essent Fatty Acids. 1993 Jan;48(1):71–78. doi: 10.1016/0952-3278(93)90012-l. [DOI] [PubMed] [Google Scholar]
  4. Bandyopadhyay G. K., Imagawa W., Wallace D., Nandi S. Linoleate metabolites enhance the in vitro proliferative response of mouse mammary epithelial cells to epidermal growth factor. J Biol Chem. 1987 Feb 25;262(6):2750–2756. [PubMed] [Google Scholar]
  5. Borgeson C. E., Pardini L., Pardini R. S., Reitz R. C. Effects of dietary fish oil on human mammary carcinoma and on lipid-metabolizing enzymes. Lipids. 1989 Apr;24(4):290–295. doi: 10.1007/BF02535165. [DOI] [PubMed] [Google Scholar]
  6. Braden L. M., Carroll K. K. Dietary polyunsaturated fat in relation to mammary carcinogenesis in rats. Lipids. 1986 Apr;21(4):285–288. doi: 10.1007/BF02536414. [DOI] [PubMed] [Google Scholar]
  7. Bégin M. E., Ells G., Das U. N., Horrobin D. F. Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst. 1986 Nov;77(5):1053–1062. [PubMed] [Google Scholar]
  8. Bégin M. E. Tumor cytotoxicity of essential fatty acids. Nutrition. 1989 Jul-Aug;5(4):258–260. [PubMed] [Google Scholar]
  9. Carter C. A., Milholland R. J., Shea W., Ip M. M. Effect of the prostaglandin synthetase inhibitor indomethacin on 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats fed different levels of fat. Cancer Res. 1983 Aug;43(8):3559–3562. [PubMed] [Google Scholar]
  10. Casabiell X., Pandiella A., Casanueva F. F. Regulation of epidermal-growth-factor-receptor signal transduction by cis-unsaturated fatty acids. Evidence for a protein kinase C-independent mechanism. Biochem J. 1991 Sep 15;278(Pt 3):679–687. doi: 10.1042/bj2780679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cave W. T., Jr Dietary n-3 (omega-3) polyunsaturated fatty acid effects on animal tumorigenesis. FASEB J. 1991 May;5(8):2160–2166. doi: 10.1096/fasebj.5.8.1673664. [DOI] [PubMed] [Google Scholar]
  12. Connolly J. M., Rose D. P. Interactions between epidermal growth factor-mediated autocrine regulation and linoleic acid-stimulated growth of a human prostate cancer cell line. Prostate. 1992;20(2):151–158. doi: 10.1002/pros.2990200210. [DOI] [PubMed] [Google Scholar]
  13. Corey E. J., Shih C., Cashman J. R. Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3581–3584. doi: 10.1073/pnas.80.12.3581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Culp B. R., Titus B. G., Lands W. E. Inhibition of prostaglandin biosynthesis by eicosapentaenoic acid. Prostaglandins Med. 1979 Nov;3(5):269–278. doi: 10.1016/0161-4630(79)90068-5. [DOI] [PubMed] [Google Scholar]
  15. Distel R. J., Robinson G. S., Spiegelman B. M. Fatty acid regulation of gene expression. Transcriptional and post-transcriptional mechanisms. J Biol Chem. 1992 Mar 25;267(9):5937–5941. [PubMed] [Google Scholar]
  16. Fazio V. M., Barrera G., Martinotti S., Farace M. G., Giglioni B., Frati L., Manzari V., Dianzani M. U. 4-Hydroxynonenal, a product of cellular lipid peroxidation, which modulates c-myc and globin gene expression in K562 erythroleukemic cells. Cancer Res. 1992 Sep 15;52(18):4866–4871. [PubMed] [Google Scholar]
  17. Gazit A., Yaish P., Gilon C., Levitzki A. Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors. J Med Chem. 1989 Oct;32(10):2344–2352. doi: 10.1021/jm00130a020. [DOI] [PubMed] [Google Scholar]
  18. Glasgow W. C., Afshari C. A., Barrett J. C., Eling T. E. Modulation of the epidermal growth factor mitogenic response by metabolites of linoleic and arachidonic acid in Syrian hamster embryo fibroblasts. Differential effects in tumor suppressor gene (+) and (-) phenotypes. J Biol Chem. 1992 May 25;267(15):10771–10779. [PubMed] [Google Scholar]
  19. Gonzalez M. J. Lipid peroxidation and tumor growth: an inverse relationship. Med Hypotheses. 1992 Jun;38(2):106–110. doi: 10.1016/0306-9877(92)90081-m. [DOI] [PubMed] [Google Scholar]
  20. Gonzalez M. J., Schemmel R. A., Dugan L., Jr, Gray J. I., Welsch C. W. Dietary fish oil inhibits human breast carcinoma growth: a function of increased lipid peroxidation. Lipids. 1993 Sep;28(9):827–832. doi: 10.1007/BF02536237. [DOI] [PubMed] [Google Scholar]
  21. Haugen A., Ryberg D., Hansteen I. L., Amstad P. Neoplastic transformation of a human kidney epithelial cell line transfected with v-Ha-ras oncogene. Int J Cancer. 1990 Mar 15;45(3):572–577. doi: 10.1002/ijc.2910450333. [DOI] [PubMed] [Google Scholar]
  22. Howe G. R., Friedenreich C. M., Jain M., Miller A. B. A cohort study of fat intake and risk of breast cancer. J Natl Cancer Inst. 1991 Mar 6;83(5):336–340. doi: 10.1093/jnci/83.5.336. [DOI] [PubMed] [Google Scholar]
  23. Hussey H. J., Tisdale M. J. Effect of polyunsaturated fatty acids on the growth of murine colon adenocarcinomas in vitro and in vivo. Br J Cancer. 1994 Jul;70(1):6–10. doi: 10.1038/bjc.1994.241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Høstmark A. T., Lystad E. Growth inhibition of human hepatoma cells (HepG2) by polyunsaturated fatty acids. Protection by albumin and vitamin E. Acta Physiol Scand. 1992 Jan;144(1):83–88. doi: 10.1111/j.1748-1716.1992.tb09270.x. [DOI] [PubMed] [Google Scholar]
  25. Kaizer L., Boyd N. F., Kriukov V., Tritchler D. Fish consumption and breast cancer risk: an ecological study. Nutr Cancer. 1989;12(1):61–68. doi: 10.1080/01635588909514002. [DOI] [PubMed] [Google Scholar]
  26. Karmali R. A. Eicosanoids in neoplasia. Prev Med. 1987 Jul;16(4):493–502. doi: 10.1016/0091-7435(87)90063-6. [DOI] [PubMed] [Google Scholar]
  27. Karmali R. A., Marsh J., Fuchs C. Effect of omega-3 fatty acids on growth of a rat mammary tumor. J Natl Cancer Inst. 1984 Aug;73(2):457–461. doi: 10.1093/jnci/73.2.457. [DOI] [PubMed] [Google Scholar]
  28. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  29. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  30. Maehle L., Eilertsen E., Mollerup S., Schønberg S., Krokan H. E., Haugen A. Effects of n-3 fatty acids during neoplastic progression and comparison of in vitro and in vivo sensitivity of two human tumour cell lines. Br J Cancer. 1995 Apr;71(4):691–696. doi: 10.1038/bjc.1995.136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Maehle L., Metcalf R. A., Ryberg D., Bennett W. P., Harris C. C., Haugen A. Altered p53 gene structure and expression in human epithelial cells after exposure to nickel. Cancer Res. 1992 Jan 1;52(1):218–221. [PubMed] [Google Scholar]
  32. Miller A. B., Howe G. R., Jain M., Craib K. J., Harrison L. Food items and food groups as risk factors in a case-control study of diet and colo-rectal cancer. Int J Cancer. 1983 Aug 15;32(2):155–161. doi: 10.1002/ijc.2910320204. [DOI] [PubMed] [Google Scholar]
  33. Mollerup S., Rivedal E., Mæhle L., Haugen A. Nickel(II) induces alterations in EGF- and TGF-beta 1-mediated growth control during malignant transformation of human kidney epithelial cells. Carcinogenesis. 1996 Feb;17(2):361–367. doi: 10.1093/carcin/17.2.361. [DOI] [PubMed] [Google Scholar]
  34. Morisaki N., Sprecher H., Milo G. E., Cornwell D. G. Fatty acid specificity in the inhibition of cell proliferation and its relationship to lipid peroxidation and prostaglandin biosynthesis. Lipids. 1982 Dec;17(12):893–899. doi: 10.1007/BF02534584. [DOI] [PubMed] [Google Scholar]
  35. Noguchi M., Kitagawa H., Miyazaki I., Mizukami Y. Influence of esculetin on incidence, proliferation, and cell kinetics of mammary carcinomas induced by 7,12-dimethylbenz[a]anthracene in rats on high- and low-fat diets. Jpn J Cancer Res. 1993 Oct;84(10):1010–1014. doi: 10.1111/j.1349-7006.1993.tb02793.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Noguchi M., Rose D. P., Earashi M., Miyazaki I. The role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma. Oncology. 1995 Jul-Aug;52(4):265–271. doi: 10.1159/000227471. [DOI] [PubMed] [Google Scholar]
  37. O'Connor D. L., Picciano M. F., Roos M. A., Easter R. A. Iron and folate utilization in reproducing swine and their progeny. J Nutr. 1989 Dec;119(12):1984–1991. doi: 10.1093/jn/119.12.1984. [DOI] [PubMed] [Google Scholar]
  38. O'Connor T. P., Roebuck B. D., Peterson F. J., Lokesh B., Kinsella J. E., Campbell T. C. Effect of dietary omega-3 and omega-6 fatty acids on development of azaserine-induced preneoplastic lesions in rat pancreas. J Natl Cancer Inst. 1989 Jun 7;81(11):858–863. doi: 10.1093/jnci/81.11.858. [DOI] [PubMed] [Google Scholar]
  39. Reddy B. S., Burill C., Rigotty J. Effect of diets high in omega-3 and omega-6 fatty acids on initiation and postinitiation stages of colon carcinogenesis. Cancer Res. 1991 Jan 15;51(2):487–491. [PubMed] [Google Scholar]
  40. Reddy B. S., Maruyama H. Effect of different levels of dietary corn oil and lard during the initiation phase of colon carcinogenesis in F344 rats. J Natl Cancer Inst. 1986 Sep;77(3):815–822. doi: 10.1093/jnci/77.3.815. [DOI] [PubMed] [Google Scholar]
  41. Roebuck B. D., Yager J. D., Jr, Longnecker D. S., Wilpone S. A. Promotion by unsaturated fat of azaserine-induced pancreatic carcinogenesis in the rat. Cancer Res. 1981 Oct;41(10):3961–3966. [PubMed] [Google Scholar]
  42. Ronai Z., Lau Y. Y., Cohen L. A. Dietary N-3 fatty acids do not affect induction of Ha-ras mutations in mammary glands of NMU-treated rats. Mol Carcinog. 1991;4(2):120–128. doi: 10.1002/mc.2940040207. [DOI] [PubMed] [Google Scholar]
  43. Rose D. P., Connolly J. M. Effects of dietary omega-3 fatty acids on human breast cancer growth and metastases in nude mice. J Natl Cancer Inst. 1993 Nov 3;85(21):1743–1747. doi: 10.1093/jnci/85.21.1743. [DOI] [PubMed] [Google Scholar]
  44. Rose D. P., Connolly J. M. Effects of fatty acids and eicosanoid synthesis inhibitors on the growth of two human prostate cancer cell lines. Prostate. 1991;18(3):243–254. doi: 10.1002/pros.2990180306. [DOI] [PubMed] [Google Scholar]
  45. Rose D. P., Connolly J. M. Effects of fatty acids and inhibitors of eicosanoid synthesis on the growth of a human breast cancer cell line in culture. Cancer Res. 1990 Nov 15;50(22):7139–7144. [PubMed] [Google Scholar]
  46. Rose D. P., Hatala M. A., Connolly J. M., Rayburn J. Effect of diets containing different levels of linoleic acid on human breast cancer growth and lung metastasis in nude mice. Cancer Res. 1993 Oct 1;53(19):4686–4690. [PubMed] [Google Scholar]
  47. Sauer L. A., Dauchy R. T. The effect of omega-6 and omega-3 fatty acids on 3H-thymidine incorporation in hepatoma 7288CTC perfused in situ. Br J Cancer. 1992 Aug;66(2):297–303. doi: 10.1038/bjc.1992.260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Speizer L. A., Watson M. J., Brunton L. L. Differential effects of omega-3 fish oils on protein kinase activities in vitro. Am J Physiol. 1991 Jul;261(1 Pt 1):E109–E114. doi: 10.1152/ajpendo.1991.261.1.E109. [DOI] [PubMed] [Google Scholar]
  49. Tiwari R. K., Mukhopadhyay B., Telang N. T., Osborne M. P. Modulation of gene expression by selected fatty acids in human breast cancer cells. Anticancer Res. 1991 Jul-Aug;11(4):1383–1388. [PubMed] [Google Scholar]
  50. Tomáska L., Resnick R. J. Suppression of platelet-derived growth factor receptor tyrosine kinase activity by unsaturated fatty acids. J Biol Chem. 1993 Mar 5;268(7):5317–5322. [PubMed] [Google Scholar]
  51. Tveito G., Hansteen I. L., Dalen H., Haugen A. Immortalization of normal human kidney epithelial cells by nickel(II). Cancer Res. 1989 Apr 1;49(7):1829–1835. [PubMed] [Google Scholar]
  52. Ullrich A., Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990 Apr 20;61(2):203–212. doi: 10.1016/0092-8674(90)90801-k. [DOI] [PubMed] [Google Scholar]
  53. de Bravo M. G., de Antueno R. J., Toledo J., De Tomás M. E., Mercuri O. F., Quintans C. Effects of an eicosapentaenoic and docosahexaenoic acid concentrate on a human lung carcinoma grown in nude mice. Lipids. 1991 Nov;26(11):866–870. doi: 10.1007/BF02535969. [DOI] [PubMed] [Google Scholar]
  54. van der Geer P., Hunter T., Lindberg R. A. Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol. 1994;10:251–337. doi: 10.1146/annurev.cb.10.110194.001343. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES