Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 Nov;86(5):1632–1640. doi: 10.1172/JCI114885

Epidermal growth factor regulates the in vitro sensitivity of human ovarian carcinoma cells to cisplatin.

R D Christen 1, D K Hom 1, D C Porter 1, P A Andrews 1, C L MacLeod 1, L Hafstrom 1, S B Howell 1
PMCID: PMC296913  PMID: 2243136

Abstract

Cisplatin (DDP) is the most effective drug for the treatment of human ovarian cancer, but the mechanisms that determine sensitivity to the cytotoxic action of DDP are not well understood. Treatment of two human ovarian carcinoma cell lines with epidermal growth factor (EGF) simultaneously increased sensitivity to DDP and caused a persistent change in morphology in the absence of any mitogenic effect. Sensitization to DDP was shown to be dependent on both EGF concentration and EGF receptor number in C127 mouse fibroblasts expressing the human EGF receptor after transfection with a pBPV plasmid construct containing the human EGF receptor gene under control of the transferrin receptor 3'-inducible regulator. Sensitization of human ovarian carcinoma cells to DDP was not blocked by inhibition of protein synthesis. EGF did not enhance sensitivity to DDP or alter morphology in DDP-resistant human ovarian carcinoma cells despite the presence of functional EGF receptors on these cells. These results showed that elements of the signal transduction pathway activated by EGF determined cellular sensitivity to DDP, and that a DDP-resistant phenotype is associated with a defect in this signal transduction pathway.

Full text

PDF
1632

Images in this article

1636Image
on p.1636
1636Image
on p.1636
1636Image
on p.1636
1636Image
on p.1636

Selected References

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

  1. Andrews P. A., Murphy M. P., Howell S. B. Differential potentiation of alkylating and platinating agent cytotoxicity in human ovarian carcinoma cells by glutathione depletion. Cancer Res. 1985 Dec;45(12 Pt 1):6250–6253. [PubMed] [Google Scholar]
  2. Andrews P. A., Schiefer M. A., Murphy M. P., Howell S. B. Enhanced potentiation of cisplatin cytotoxicity in human ovarian carcinoma cells by prolonged glutathione depletion. Chem Biol Interact. 1988;65(1):51–58. doi: 10.1016/0009-2797(88)90030-0. [DOI] [PubMed] [Google Scholar]
  3. Bauknecht T., Runge M., Schwall M., Pfleiderer A. Occurrence of epidermal growth factor receptors in human adnexal tumors and their prognostic value in advanced ovarian carcinomas. Gynecol Oncol. 1988 Feb;29(2):147–157. doi: 10.1016/0090-8258(88)90209-0. [DOI] [PubMed] [Google Scholar]
  4. Bell R. M. Protein kinase C activation by diacylglycerol second messengers. Cell. 1986 Jun 6;45(5):631–632. doi: 10.1016/0092-8674(86)90774-9. [DOI] [PubMed] [Google Scholar]
  5. Bravo R., Burckhardt J., Curran T., Müller R. Stimulation and inhibition of growth by EGF in different A431 cell clones is accompanied by the rapid induction of c-fos and c-myc proto-oncogenes. EMBO J. 1985 May;4(5):1193–1197. doi: 10.1002/j.1460-2075.1985.tb03759.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bridges K. R., Cudkowicz A. Effect of iron chelators on the transferrin receptor in K562 cells. J Biol Chem. 1984 Nov 10;259(21):12970–12977. [PubMed] [Google Scholar]
  7. Brooks R. F. Continuous protein synthesis is required to maintain the probability of entry into S phase. Cell. 1977 Sep;12(1):311–317. doi: 10.1016/0092-8674(77)90209-4. [DOI] [PubMed] [Google Scholar]
  8. Carpenter G., Cohen S. Epidermal growth factor. Annu Rev Biochem. 1979;48:193–216. doi: 10.1146/annurev.bi.48.070179.001205. [DOI] [PubMed] [Google Scholar]
  9. DiSaia P. J., Sinkovics J. G., Rutledge F. N., Smith J. P. Cell-mediated immunity to human malignant cells. A brief review and further studies with two gynecologic tumors. Am J Obstet Gynecol. 1972 Dec 1;114(7):979–989. doi: 10.1016/0002-9378(72)90109-3. [DOI] [PubMed] [Google Scholar]
  10. Diamond I., Legg A., Schneider J. A., Rozengurt E. Glycolysis in quiescent cultures of 3T3 cells. Stimulation by serum, epidermal growth factor, and insulin in intact cells and persistence of the stimulation after cell homogenization. J Biol Chem. 1978 Feb 10;253(3):866–871. [PubMed] [Google Scholar]
  11. Fernandez-Pol J. A., Hamilton P. D., Klos D. J. Transcriptional regulation of proto-oncogene expression by epidermal growth factor, transforming growth factor beta 1, and triiodothyronine in MDA-468 cells. J Biol Chem. 1989 Mar 5;264(7):4151–4156. [PubMed] [Google Scholar]
  12. Fernandez-Pol J. A., Talkad V. D., Klos D. J., Hamilton P. D. Suppression of the EGF-dependent induction of c-myc proto-oncogene expression by transforming growth factor beta in a human breast carcinoma cell line. Biochem Biophys Res Commun. 1987 May 14;144(3):1197–1205. doi: 10.1016/0006-291x(87)91438-0. [DOI] [PubMed] [Google Scholar]
  13. Gottesman M. M., Pastan I. The multidrug transporter, a double-edged sword. J Biol Chem. 1988 Sep 5;263(25):12163–12166. [PubMed] [Google Scholar]
  14. Greenberg M. E., Ziff E. B. Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature. 1984 Oct 4;311(5985):433–438. doi: 10.1038/311433a0. [DOI] [PubMed] [Google Scholar]
  15. Hamilton T. C., Winker M. A., Louie K. G., Batist G., Behrens B. C., Tsuruo T., Grotzinger K. R., McKoy W. M., Young R. C., Ozols R. F. Augmentation of adriamycin, melphalan, and cisplatin cytotoxicity in drug-resistant and -sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated glutathione depletion. Biochem Pharmacol. 1985 Jul 15;34(14):2583–2586. doi: 10.1016/0006-2952(85)90551-9. [DOI] [PubMed] [Google Scholar]
  16. Honegger A. M., Dull T. J., Felder S., Van Obberghen E., Bellot F., Szapary D., Schmidt A., Ullrich A., Schlessinger J. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing. Cell. 1987 Oct 23;51(2):199–209. doi: 10.1016/0092-8674(87)90147-4. [DOI] [PubMed] [Google Scholar]
  17. Honegger A. M., Szapary D., Schmidt A., Lyall R., Van Obberghen E., Dull T. J., Ullrich A., Schlessinger J. A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis. Mol Cell Biol. 1987 Dec;7(12):4568–4571. doi: 10.1128/mcb.7.12.4568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hospers G. A., Mulder N. H., de Jong B., de Ley L., Uges D. R., Fichtinger-Schepman A. M., Scheper R. J., de Vries E. G. Characterization of a human small cell lung carcinoma cell line with acquired resistance to cis-diamminedichloroplatinum(II) in vitro. Cancer Res. 1988 Dec 1;48(23):6803–6807. [PubMed] [Google Scholar]
  19. Hromas R. A., Andrews P. A., Murphy M. P., Burns C. P. Glutathione depletion reverses cisplatin resistance in murine L1210 leukemia cells. Cancer Lett. 1987 Jan;34(1):9–13. doi: 10.1016/0304-3835(87)90067-x. [DOI] [PubMed] [Google Scholar]
  20. Imai Y., Leung C. K., Friesen H. G., Shiu R. P. Epidermal growth factor receptors and effect of epidermal growth factor on growth of human breast cancer cells in long-term tissue culture. Cancer Res. 1982 Nov;42(11):4394–4398. [PubMed] [Google Scholar]
  21. Inoue K., Mukaiyama T., Mitsui I., Ogawa M. In vitro evaluation of anticancer drugs in relation to development of drug resistance in the human tumor clonogenic assay. Cancer Chemother Pharmacol. 1985;15(3):208–213. doi: 10.1007/BF00263887. [DOI] [PubMed] [Google Scholar]
  22. Isonishi S., Andrews P. A., Howell S. B. Increased sensitivity to cis-diamminedichloroplatinum(II) in human ovarian carcinoma cells in response to treatment with 12-O-tetradecanoylphorbol 13-acetate. J Biol Chem. 1990 Mar 5;265(7):3623–3627. [PubMed] [Google Scholar]
  23. Kamata N., Chida K., Rikimaru K., Horikoshi M., Enomoto S., Kuroki T. Growth-inhibitory effects of epidermal growth factor and overexpression of its receptors on human squamous cell carcinomas in culture. Cancer Res. 1986 Apr;46(4 Pt 1):1648–1653. [PubMed] [Google Scholar]
  24. Kaufman R. J., Brown P. C., Schimke R. T. Amplified dihydrofolate reductase genes in unstably methotrexate-resistant cells are associated with double minute chromosomes. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5669–5673. doi: 10.1073/pnas.76.11.5669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kawamoto T., Sato J. D., Le A., McClure D. B., Sato G. H. Development of a serum-free medium for growth of NS-1 mouse myeloma cells and its application to the isolation of NS-1 hybridomas. Anal Biochem. 1983 Apr 15;130(2):445–453. doi: 10.1016/0003-2697(83)90614-0. [DOI] [PubMed] [Google Scholar]
  26. Kawamoto T., Sato J. D., Le A., Polikoff J., Sato G. H., Mendelsohn J. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci U S A. 1983 Mar;80(5):1337–1341. doi: 10.1073/pnas.80.5.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kruijer W., Cooper J. A., Hunter T., Verma I. M. Platelet-derived growth factor induces rapid but transient expression of the c-fos gene and protein. Nature. 1984 Dec 20;312(5996):711–716. doi: 10.1038/312711a0. [DOI] [PubMed] [Google Scholar]
  28. Kwok T. T., Sutherland R. M. Enhancement of sensitivity of human squamous carcinoma cells to radiation by epidermal growth factor. J Natl Cancer Inst. 1989 Jul 5;81(13):1020–1024. doi: 10.1093/jnci/81.13.1020. [DOI] [PubMed] [Google Scholar]
  29. Levine L., Hassid A. Epidermal growth factor stimulates prostaglandin biosynthesis by canine kidney (MDCK) cells. Biochem Biophys Res Commun. 1977 Jun 20;76(4):1181–1187. doi: 10.1016/0006-291x(77)90980-9. [DOI] [PubMed] [Google Scholar]
  30. Libermann T. A., Razon N., Bartal A. D., Yarden Y., Schlessinger J., Soreq H. Expression of epidermal growth factor receptors in human brain tumors. Cancer Res. 1984 Feb;44(2):753–760. [PubMed] [Google Scholar]
  31. Masuda H., Ozols R. F., Lai G. M., Fojo A., Rothenberg M., Hamilton T. C. Increased DNA repair as a mechanism of acquired resistance to cis-diamminedichloroplatinum (II) in human ovarian cancer cell lines. Cancer Res. 1988 Oct 15;48(20):5713–5716. [PubMed] [Google Scholar]
  32. McClelland A., Kühn L. C., Ruddle F. H. The human transferrin receptor gene: genomic organization, and the complete primary structure of the receptor deduced from a cDNA sequence. Cell. 1984 Dec;39(2 Pt 1):267–274. doi: 10.1016/0092-8674(84)90004-7. [DOI] [PubMed] [Google Scholar]
  33. Meyers M. B., Shen W. P., Spengler B. A., Ciccarone V., O'Brien J. P., Donner D. B., Furth M. E., Biedler J. L. Increased epidermal growth factor receptor in multidrug-resistant human neuroblastoma cells. J Cell Biochem. 1988 Oct;38(2):87–97. doi: 10.1002/jcb.240380203. [DOI] [PubMed] [Google Scholar]
  34. Moolenaar W. H., Tertoolen L. G., de Laat S. W. Growth factors immediately raise cytoplasmic free Ca2+ in human fibroblasts. J Biol Chem. 1984 Jul 10;259(13):8066–8069. [PubMed] [Google Scholar]
  35. Mukku V. R., Stancel G. M. Regulation of epidermal growth factor receptor by estrogen. J Biol Chem. 1985 Aug 15;260(17):9820–9824. [PubMed] [Google Scholar]
  36. Mulder E., van Loon D., de Boer W., Schuurmans A. L., Bolt J., Voorhorst M. M., Kuiper G. G., Brinkmann A. O. Mechanism of androgen action: recent observations on the domain structure of androgen receptors and the induction of EGF-receptors by androgens in prostate tumor cells. J Steroid Biochem. 1989 Jan;32(1B):151–156. doi: 10.1016/0022-4731(89)90156-8. [DOI] [PubMed] [Google Scholar]
  37. Murphy L. C., Murphy L. J., Shiu R. P. Progestin regulation of EGF-receptor mRNA accumulation in T-47D human breast cancer cells. Biochem Biophys Res Commun. 1988 Jan 15;150(1):192–196. doi: 10.1016/0006-291x(88)90504-9. [DOI] [PubMed] [Google Scholar]
  38. Müller R., Bravo R., Burckhardt J., Curran T. Induction of c-fos gene and protein by growth factors precedes activation of c-myc. Nature. 1984 Dec 20;312(5996):716–720. doi: 10.1038/312716a0. [DOI] [PubMed] [Google Scholar]
  39. Novak-Hofer I., Thomas G. Epidermal growth factor-mediated activation of an S6 kinase in Swiss mouse 3T3 cells. J Biol Chem. 1985 Aug 25;260(18):10314–10319. [PubMed] [Google Scholar]
  40. Owen D., Kühn L. C. Noncoding 3' sequences of the transferrin receptor gene are required for mRNA regulation by iron. EMBO J. 1987 May;6(5):1287–1293. doi: 10.1002/j.1460-2075.1987.tb02366.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Pandiella A., Magni M., Lovisolo D., Meldolesi J. The effect of epidermal growth factor on membrane potential. Rapid hyperpolarization followed by persistent fluctuations. J Biol Chem. 1989 Aug 5;264(22):12914–12921. [PubMed] [Google Scholar]
  42. Pike L. J., Eakes A. T. Epidermal growth factor stimulates the production of phosphatidylinositol monophosphate and the breakdown of polyphosphoinositides in A431 cells. J Biol Chem. 1987 Feb 5;262(4):1644–1651. [PubMed] [Google Scholar]
  43. Rozengurt E. Stimulation of Na influx, Na-K pump activity and DNA synthesis in quiescent cultured cells. Adv Enzyme Regul. 1980;19:61–85. doi: 10.1016/0065-2571(81)90009-1. [DOI] [PubMed] [Google Scholar]
  44. Sato J. D., Kawamoto T., Le A. D., Mendelsohn J., Polikoff J., Sato G. H. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med. 1983 Dec;1(5):511–529. [PubMed] [Google Scholar]
  45. Sawyer S. T., Cohen S. Enhancement of calcium uptake and phosphatidylinositol turnover by epidermal growth factor in A-431 cells. Biochemistry. 1981 Oct 13;20(21):6280–6286. doi: 10.1021/bi00524a057. [DOI] [PubMed] [Google Scholar]
  46. Schlessinger J., Schreiber A. B., Levi A., Lax I., Libermann T., Yarden Y. Regulation of cell proliferation by epidermal growth factor. CRC Crit Rev Biochem. 1983;14(2):93–111. doi: 10.3109/10409238309102791. [DOI] [PubMed] [Google Scholar]
  47. Scudiero D. A., Shoemaker R. H., Paull K. D., Monks A., Tierney S., Nofziger T. H., Currens M. J., Seniff D., Boyd M. R. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res. 1988 Sep 1;48(17):4827–4833. [PubMed] [Google Scholar]
  48. Simmonds A. P., McDonald E. C. Ovarian carcinoma cells in culture: assessment of drug sensitivity by clonogenic assay. Br J Cancer. 1984 Sep;50(3):317–326. doi: 10.1038/bjc.1984.178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Stastny M., Cohen S. Epidermal growth factor. IV. The induction of ornithine decarboxylase. Biochim Biophys Acta. 1970 Apr 15;204(2):578–589. [PubMed] [Google Scholar]
  50. Sunada H., Magun B. E., Mendelsohn J., MacLeod C. L. Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3825–3829. doi: 10.1073/pnas.83.11.3825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Thomas G., Gordon J. Regulation of protein synthesis during the shift of quiescent animal cells into the proliferative state. Cell Biol Int Rep. 1979 Jul;3(4):307–320. doi: 10.1016/s0309-1651(79)80001-6. [DOI] [PubMed] [Google Scholar]
  52. Thompson K. L., Rosner M. R. Regulation of epidermal growth factor receptor gene expression by retinoic acid and epidermal growth factor. J Biol Chem. 1989 Feb 25;264(6):3230–3234. [PubMed] [Google Scholar]
  53. Waud W. R. Differential uptake of cis-diamminedichloroplatinum (II) by sensitive and resistant murine L1210 leukemia cells. Cancer Res. 1987 Dec 15;47(24 Pt 1):6549–6555. [PubMed] [Google Scholar]
  54. Wilkinson M. F., MacLeod C. L. Complex regulation of the T cell receptor alpha gene: three different modes of triggering induction. Eur J Immunol. 1988 Jun;18(6):873–879. doi: 10.1002/eji.1830180607. [DOI] [PubMed] [Google Scholar]
  55. Willingham M. C., Maxfield F. R., Pastan I. H. alpha 2 Macroglobulin binding to the plasma membrane of cultured fibroblasts. Diffuse binding followed by clustering in coated regions. J Cell Biol. 1979 Sep;82(3):614–625. doi: 10.1083/jcb.82.3.614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Wilson A. P., Ford C. H., Newman C. E., Howell A. cis-platinum and ovarian carcinoma. In vitro chemosensitivity of cultured tumour cells from patients receiving high dose cis-platinum as first line treatment. Br J Cancer. 1987 Dec;56(6):763–773. doi: 10.1038/bjc.1987.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Wolf C. R., Hayward I. P., Lawrie S. S., Buckton K., McIntyre M. A., Adams D. J., Lewis A. D., Scott A. R., Smyth J. F. Cellular heterogeneity and drug resistance in two ovarian adenocarcinoma cell lines derived from a single patient. Int J Cancer. 1987 Jun 15;39(6):695–702. doi: 10.1002/ijc.2910390607. [DOI] [PubMed] [Google Scholar]
  58. Woods L. K., Morgan R. T., Quinn L. A., Moore G. E., Semple T. U., Stedman K. E. Comparison of four new cell lines from patients with adenocarcinoma of the ovary. Cancer Res. 1979 Nov;39(11):4449–4459. [PubMed] [Google Scholar]
  59. Xu Y. H., Richert N., Ito S., Merlino G. T., Pastan I. Characterization of epidermal growth factor receptor gene expression in malignant and normal human cell lines. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7308–7312. doi: 10.1073/pnas.81.23.7308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. de Jong W. H., Steerenberg P. A., Vos J. G., Bulten E. J., Verbeek F., Kruizinga W., Ruitenberg E. J. Antitumor activity, induction of cross-resistance, and nephrotoxicity of a new platinum analogue, cis-1,1-diaminomethylcyclohexaneplatinum(II) sulfate, and of cis-diamminedichloroplatinum(II) in an immunocytoma model in the LOU/M rat. Cancer Res. 1983 Oct;43(10):4927–4934. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES