Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Oct 1;90(19):8972–8976. doi: 10.1073/pnas.90.19.8972

Inverse regulation of human ERBB2 and epidermal growth factor receptors by tumor necrosis factor alpha.

H Kalthoff 1, C Roeder 1, J Gieseking 1, I Humburg 1, W Schmiegel 1
PMCID: PMC47483  PMID: 8105469

Abstract

Recombinant human tumor necrosis factor (TNF) alpha decreased the expression of ERBB2 mRNA by stimulating p55 TNF receptors of pancreatic tumor cells. This decrease contrasts with an increase in epidermal growth factor receptor (EGFR) mRNA. Both effects were selectively achieved by TNF-alpha or -beta, whereas interferon alpha or gamma or transforming growth factor beta showed no such effects. The inverse regulatory effects of TNF on ERBB2 and EGFR mRNA levels were evoked by different signaling pathways of p55 TNF receptors. The TNF-mediated ERBB2 mRNA decrease was followed by a reduction in protein. Four of five pancreatic tumor cell lines exhibited this down-regulation. This decrease of ERBB2 is a singular example of a modulation of this growth factor receptor by TNF. Overexpression of ERBB2 has been reported to cause resistance to TNF and other cytotoxic cytokines. In our study we show that the TNF-mediated down-regulation of ERBB2 in pancreatic tumor cells is accompanied by an increase in growth inhibition at low doses of TNF. The simultaneous alteration of the ERBB2/EGFR balance by TNF represents a striking model of cytokine receptor transregulation in the growth control of malignant pancreatic epithelial cells.

Full text

PDF
8972

Images in this article

8973Fig. 1
on p.8973
8973Fig. 2
on p.8973
8974Fig. 3
on p.8974
8974Fig. 4
on p.8974
8974Fig. 5
on p.8974

Selected References

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

  1. Bargmann C. I., Hung M. C., Weinberg R. A. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature. 1986 Jan 16;319(6050):226–230. doi: 10.1038/319226a0. [DOI] [PubMed] [Google Scholar]
  2. Brockhaus M., Schoenfeld H. J., Schlaeger E. J., Hunziker W., Lesslauer W., Loetscher H. Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3127–3131. doi: 10.1073/pnas.87.8.3127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Clark G. M., McGuire W. L. Follow-up study of HER-2/neu amplification in primary breast cancer. Cancer Res. 1991 Feb 1;51(3):944–948. [PubMed] [Google Scholar]
  4. Dati C., Antoniotti S., Taverna D., Perroteau I., De Bortoli M. Inhibition of c-erbB-2 oncogene expression by estrogens in human breast cancer cells. Oncogene. 1990 Jul;5(7):1001–1006. [PubMed] [Google Scholar]
  5. Dobashi K., Davis J. G., Mikami Y., Freeman J. K., Hamuro J., Greene M. I. Characterization of a neu/c-erbB-2 protein-specific activating factor. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8582–8586. doi: 10.1073/pnas.88.19.8582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fiers W. Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level. FEBS Lett. 1991 Jul 22;285(2):199–212. doi: 10.1016/0014-5793(91)80803-b. [DOI] [PubMed] [Google Scholar]
  7. Goldman R., Levy R. B., Peles E., Yarden Y. Heterodimerization of the erbB-1 and erbB-2 receptors in human breast carcinoma cells: a mechanism for receptor transregulation. Biochemistry. 1990 Dec 18;29(50):11024–11028. doi: 10.1021/bi00502a002. [DOI] [PubMed] [Google Scholar]
  8. Haliday E. M., Ramesha C. S., Ringold G. TNF induces c-fos via a novel pathway requiring conversion of arachidonic acid to a lipoxygenase metabolite. EMBO J. 1991 Jan;10(1):109–115. doi: 10.1002/j.1460-2075.1991.tb07926.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hall P. A., Hughes C. M., Staddon S. L., Richman P. I., Gullick W. J., Lemoine N. R. The c-erb B-2 proto-oncogene in human pancreatic cancer. J Pathol. 1990 Jul;161(3):195–200. doi: 10.1002/path.1711610305. [DOI] [PubMed] [Google Scholar]
  10. Holmes W. E., Sliwkowski M. X., Akita R. W., Henzel W. J., Lee J., Park J. W., Yansura D., Abadi N., Raab H., Lewis G. D. Identification of heregulin, a specific activator of p185erbB2. Science. 1992 May 22;256(5060):1205–1210. doi: 10.1126/science.256.5060.1205. [DOI] [PubMed] [Google Scholar]
  11. Hudziak R. M., Lewis G. D., Shalaby M. R., Eessalu T. E., Aggarwal B. B., Ullrich A., Shepard H. M. Amplified expression of the HER2/ERBB2 oncogene induces resistance to tumor necrosis factor alpha in NIH 3T3 cells. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5102–5106. doi: 10.1073/pnas.85.14.5102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hudziak R. M., Lewis G. D., Winget M., Fendly B. M., Shepard H. M., Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989 Mar;9(3):1165–1172. doi: 10.1128/mcb.9.3.1165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hynes N. E., Taverna D., Harwerth I. M., Ciardiello F., Salomon D. S., Yamamoto T., Groner B. Epidermal growth factor receptor, but not c-erbB-2, activation prevents lactogenic hormone induction of the beta-casein gene in mouse mammary epithelial cells. Mol Cell Biol. 1990 Aug;10(8):4027–4034. doi: 10.1128/mcb.10.8.4027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kalthoff H., Roeder C., Brockhaus M., Thiele H. G., Schmiegel W. Tumor necrosis factor (TNF) up-regulates the expression of p75 but not p55 TNF receptors, and both receptors mediate, independently of each other, up-regulation of transforming growth factor alpha and epidermal growth factor receptor mRNA. J Biol Chem. 1993 Feb 5;268(4):2762–2766. [PubMed] [Google Scholar]
  15. Kalthoff H., Roeder C., Humburg I., Thiele H. G., Greten H., Schmiegel W. Modulation of platelet-derived growth factor A- and B-chain/c-sis mRNA by tumor necrosis factor and other agents in adenocarcinoma cells. Oncogene. 1991 Jun;6(6):1015–1021. [PubMed] [Google Scholar]
  16. Kalthoff H., Schmiegel W., Roeder C., Kasche D., Schmidt A., Lauer G., Thiele H. G., Honold G., Pantel K., Riethmüller G. p53 and K-RAS alterations in pancreatic epithelial cell lesions. Oncogene. 1993 Feb;8(2):289–298. [PubMed] [Google Scholar]
  17. Kern J. A., Schwartz D. A., Nordberg J. E., Weiner D. B., Greene M. I., Torney L., Robinson R. A. p185neu expression in human lung adenocarcinomas predicts shortened survival. Cancer Res. 1990 Aug 15;50(16):5184–5187. [PubMed] [Google Scholar]
  18. Kokai Y., Myers J. N., Wada T., Brown V. I., LeVea C. M., Davis J. G., Dobashi K., Greene M. I. Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts. Cell. 1989 Jul 28;58(2):287–292. doi: 10.1016/0092-8674(89)90843-x. [DOI] [PubMed] [Google Scholar]
  19. Kornilova E. S., Taverna D., Hoeck W., Hynes N. E. Surface expression of erbB-2 protein is post-transcriptionally regulated in mammary epithelial cells by epidermal growth factor and by the culture density. Oncogene. 1992 Mar;7(3):511–519. [PubMed] [Google Scholar]
  20. Kraus M. H., Issing W., Miki T., Popescu N. C., Aaronson S. A. Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9193–9197. doi: 10.1073/pnas.86.23.9193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lemoine N. R., Hughes C. M., Barton C. M., Poulsom R., Jeffery R. E., Klöppel G., Hall P. A., Gullick W. J. The epidermal growth factor receptor in human pancreatic cancer. J Pathol. 1992 Jan;166(1):7–12. doi: 10.1002/path.1711660103. [DOI] [PubMed] [Google Scholar]
  22. Lichtenstein A., Berenson J., Gera J. F., Waldburger K., Martinez-Maza O., Berek J. S. Resistance of human ovarian cancer cells to tumor necrosis factor and lymphokine-activated killer cells: correlation with expression of HER2/neu oncogenes. Cancer Res. 1990 Nov 15;50(22):7364–7370. [PubMed] [Google Scholar]
  23. Lichtenstein A., Fady C., Gera J. F., Gardner A., Chazin V. R., Kelley D., Berenson J. Effects of beta-2 microglobulin anti-sense oligonucleotides on sensitivity of HER2/neu oncogene-expressing and nonexpressing target cells to lymphocyte-mediated lysis. Cell Immunol. 1992 Apr 15;141(1):219–232. doi: 10.1016/0008-8749(92)90141-b. [DOI] [PubMed] [Google Scholar]
  24. Lichtenstein A., Gera J. F., Andrews J., Berenson J., Ware C. F. Inhibitors of ADP-ribose polymerase decrease the resistance of HER2/neu-expressing cancer cells to the cytotoxic effects of tumor necrosis factor. J Immunol. 1991 Mar 15;146(6):2052–2058. [PubMed] [Google Scholar]
  25. Lupu R., Colomer R., Kannan B., Lippman M. E. Characterization of a growth factor that binds exclusively to the erbB-2 receptor and induces cellular responses. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2287–2291. doi: 10.1073/pnas.89.6.2287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lupu R., Colomer R., Zugmaier G., Sarup J., Shepard M., Slamon D., Lippman M. E. Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. Science. 1990 Sep 28;249(4976):1552–1555. doi: 10.1126/science.2218496. [DOI] [PubMed] [Google Scholar]
  27. Marth C., Cronauer M. V., Doppler W., Ofner D., Ullrich A., Daxenbichler G. Effects of interferons on the expression of the proto-oncogene HER-2 in human ovarian carcinoma cells. Int J Cancer. 1992 Jan 2;50(1):64–68. doi: 10.1002/ijc.2910500114. [DOI] [PubMed] [Google Scholar]
  28. Marth C., Müller-Holzner E., Greiter E., Cronauer M. V., Zeimet A. G., Doppler W., Eibl B., Hynes N. E., Daxenbichler G. Gamma-interferon reduces expression of the protooncogene c-erbB-2 in human ovarian carcinoma cells. Cancer Res. 1990 Nov 1;50(21):7037–7041. [PubMed] [Google Scholar]
  29. Quian X. L., Decker S. J., Greene M. I. p185c-neu and epidermal growth factor receptor associate into a structure composed of activated kinases. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1330–1334. doi: 10.1073/pnas.89.4.1330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Raitano A. B., Scuderi P., Korc M. Long-term effect of tumor necrosis factor and gamma interferon in human pancreatic carcinoma cells. Int J Pancreatol. 1990 Mar;6(2):109–118. doi: 10.1007/BF02933045. [DOI] [PubMed] [Google Scholar]
  31. Read L. D., Keith D., Jr, Slamon D. J., Katzenellenbogen B. S. Hormonal modulation of HER-2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines. Cancer Res. 1990 Jul 1;50(13):3947–3951. [PubMed] [Google Scholar]
  32. Salomon D. S., Kim N., Saeki T., Ciardiello F. Transforming growth factor-alpha: an oncodevelopmental growth factor. Cancer Cells. 1990 Dec;2(12):389–397. [PubMed] [Google Scholar]
  33. Schechter A. L., Stern D. F., Vaidyanathan L., Decker S. J., Drebin J. A., Greene M. I., Weinberg R. A. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984 Dec 6;312(5994):513–516. doi: 10.1038/312513a0. [DOI] [PubMed] [Google Scholar]
  34. Schmiegel W. H., Caesar J., Kalthoff H., Greten H., Schreiber H. W., Thiele H. G. Antiproliferative effects exerted by recombinant human tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on human pancreatic tumor cell lines. Pancreas. 1988;3(2):180–188. doi: 10.1097/00006676-198804000-00012. [DOI] [PubMed] [Google Scholar]
  35. Schmiegel W., Roeder C., Schmielau J., Rodeck U., Kalthoff H. Tumor necrosis factor alpha induces the expression of transforming growth factor alpha and the epidermal growth factor receptor in human pancreatic cancer cells. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):863–867. doi: 10.1073/pnas.90.3.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shoyab M., Plowman G. D., McDonald V. L., Bradley J. G., Todaro G. J. Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science. 1989 Feb 24;243(4894 Pt 1):1074–1076. doi: 10.1126/science.2466334. [DOI] [PubMed] [Google Scholar]
  37. Slamon D. J., Godolphin W., Jones L. A., Holt J. A., Wong S. G., Keith D. E., Levin W. J., Stuart S. G., Udove J., Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
  38. Sporn M. B., Roberts A. B. Peptide growth factors are multifunctional. Nature. 1988 Mar 17;332(6161):217–219. doi: 10.1038/332217a0. [DOI] [PubMed] [Google Scholar]
  39. Tarakhovsky A., Zaichuk T., Prassolov V., Butenko Z. A. A 25 kDa polypeptide is the ligand for p185neu and is secreted by activated macrophages. Oncogene. 1991 Dec;6(12):2187–2196. [PubMed] [Google Scholar]
  40. 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]
  41. Wada T., Qian X. L., Greene M. I. Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell. 1990 Jun 29;61(7):1339–1347. doi: 10.1016/0092-8674(90)90697-d. [DOI] [PubMed] [Google Scholar]
  42. Williams T. M., Weiner D. B., Greene M. I., Maguire H. C., Jr Expression of c-erbB-2 in human pancreatic adenocarcinomas. Pathobiology. 1991;59(1):46–52. doi: 10.1159/000163614. [DOI] [PubMed] [Google Scholar]
  43. Yonemura Y., Ninomiya I., Yamaguchi A., Fushida S., Kimura H., Ohoyama S., Miyazaki I., Endou Y., Tanaka M., Sasaki T. Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res. 1991 Feb 1;51(3):1034–1038. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES