Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Regulation of Cyclooxygenase-2 pathway by HER2 receptor

Oncogene volume 18, pages 305–314 (1999)Cite this article

Abstract

Emerging lines of evidence suggest that in addition to growth factors, the process of colorectal tumorigenesis may also be driven by the upregulation of the inducible form of cyclooxygenase-2 (COX-2), an enzyme responsible for the conversion of arachidonic acid to PGEs. The present study was undertaken to investigate the expression and activation of the HER family members, and to explore the regulation of COX-2 expression by the HER2 pathway in human colorectal cancer cells. Here, we report that human colorectal cancer cell lines express abundant levels of HER2 and HER3 receptors, and are growth-stimulated by recombinant neu-differentiation factor-beta 1 (NDF). NDF-treatment of colorectal cancer cells was accompanied by increased tyrosine phosphorylation and heterodimerization of HER3 with HER2. In addition, we demonstrated that HER2 and HER3 receptors in colorectal cancer cells are constitutively phosphorylated on tyrosine residues and form heterodimeric complexes in the absence of exogenous NDF. Inhibition of HER2/HER3 signaling by an anti-HER3 mAb against the ligand binding site resulted in a decrease in the levels of constitutively activated HER2/HER3 heterodimers, and the unexpected reduction of COX-2 expression. Activation of the HER2/HER3 pathway by NDF induced the activation of COX-2 promoter, expression of COX-2 mRNA, COX-2 protein and accumulation of prostaglandin E2 in the culture medium. Finally, we demonstrated that NDF promotes the ability of colorectal cancer cells to survive in an extracellular matrix milieu, such as Matrigel, and also to invade through a 8 μm porous membrane. These biological activities of NDF and its stimulation of cell proliferation are blocked by a specific inhibitor of COX-2. Taken together, our findings provide the first biochemical evidence of a possible role of the COX-2 pathway in the mitogenic action of NDF in colorectal cancer cells where it may be constitutively upregulated due to the autocrine/paracrine activation of HER2/HER3 heterodimers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 9
Figure 8

Similar content being viewed by others

Abbreviations

NDF:

recombinant neu-differentiation factor-beta 1

COX-2:

cyclooxygenase-2

mAb:

monoclonal antibody

PGE2:

prostaglandin E2

References

  • Adam L, Crepin M, Lelong J, Spanakis E and Israel L. . 1994 Int. J. Cancer 59: 262–268.

    Article  CAS  Google Scholar 

  • Alroy I and Yarden Y. . 1997 FEBS Lett. 410: 83–86.

  • Anzano M, Rieman D, Pritchett W, Bowen-Pope D and Grieg R. . 1989 Cancer Res. 49: 2898–2904.

  • Boolbol SK, Dannenberg AJ, Chadburn A, Martucci C, Guo X, Ramonetti JT, Abreu-Goris M, Newmark HL, Lipkin ML, DeCosse JJ and Bertagnolli MM. . 1996 Cancer Res. 56: 2556–2560.

  • Brattain MG, Levine AE, Chakrabarty S, Yeoman LC, Willson JKV and Long B. . 1984 Cancer Metast. Rev. 3: 177–191.

  • Carraway III KL, Soltoff SP, Diamonti AJ and Cantley LC. . 1995 J. Biol. Chem. 270: 7111–7116.

    Article  CAS  Google Scholar 

  • Carraway III KL and Cantley LC. . 1994 Cell 78: 5–8.

    Article  CAS  Google Scholar 

  • Chiu C, McEntee MF and Whelan J. . 1997 Cancer Res. 57: 4267–4273.

  • Chen Q, Miyaura C, Higashi S, Murakami M, Kudo I, Saito S, Hiraide T, Shibasaki Y and Suda I. . 1997 J. Biol. Chem. 272: 5952–5958.

    Article  CAS  Google Scholar 

  • Chen X, Levkowitz G, Tzabart E, Karunagaran D, Lavi S, Ben-Baruch N, Leitner O, Ratzkin BJ, Bacus SS and Yarden Y. . 1996 J. Biol. Chem. 271: 7620–7629.

    Article  CAS  Google Scholar 

  • Ciardiello F, Kim N, Saeki T, Dono R, Persico MG, Plowman GD, Garrigues J, Radke S, Todaro GJ and Salomon DS. . 1991 Proc. Natl. Acad. Sci. USA 88: 7792–7796.

  • Coffey RJ, Hawkey CJ, Damstrup L, Graves-Deal R, Daniel VC, Dempsey PJ, Chinery R, Kirkland SC, DuBois RN, Jetton TL and Morrow JD. . 1997 Proc. Natl. Acad. Sci. USA 94: 657–662.

  • Coffey R, Goustin A, Soderquiat S, Shipley G, Wolfshohl J, Carpenter G and Moses H. . 1987 Cancer Res. 47: 4590–4594.

  • DuBois RN, Radhika A, Reddy BS and Entingh AJ. . 1996 Gastroenterology 110: 1259–1262.

    Article  CAS  Google Scholar 

  • DuBois RN, Awad J, Morrow J, Roberts II LJ and Bishop PR. . 1994 J. Clin. Invest. 93: 493–498.

    Article  CAS  Google Scholar 

  • Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S and DuBois RN. . 1994 Gastroenterology 107: 1183–1188.

    Article  CAS  Google Scholar 

  • Fanger BO, Stephens JE and Staros JV. . 1989 FASEB J. 3: 71–75.

  • Granstrom E and Kindahl H. . 1978 Adv. Prostagland. Thromb. Res. 5: 119.

  • Graus-Porta D, Beerli RR, Daly JM and Hynes NE. . 1997 EMBO J. 16: 1647–1655.

  • Guy PM, Platko JV, Cantley LC, Cerione RA and Carraway III KL. . 1994 Proc. Natl. Acad. Sci. USA 91: 8132–8136.

  • Horan T, Wen J, Arakawa T, Liu NL, Brankow D, Hu S, Ratzkin B and Philo JS. . 1995 J. Biol. Chem. 270: 24604–24608.

    Article  CAS  Google Scholar 

  • Hynes NC and Stern DF. . 1994 Biochim. Biophys. Acta. 1198: 165–184.

  • Kapitanovic S, Radosevic S, Kapitanovic M, Andelinovic S, Ferencic Z, Tavassoli M, Primorac D, Sonicki Z, Spaventi S, Pavelic K and Spaventi R. . 1997 Gastroenterology 112: 1103–1113.

    Article  CAS  Google Scholar 

  • Keating MT and Williams LT. . 1988 Science 239: 914–916.

    Article  CAS  Google Scholar 

  • Kumar R, Shepard HM and Mendelsohn J. . 1991 Mol. Cell. Biol. 11: 979–986.

    Article  CAS  Google Scholar 

  • Kumar R, Mandal M, Ratzkin BJ, Liu N and Lipton A. . 1996 J. Cell. Biochem. 239: 914–916.

  • Kumar R and Atlas I. . 1992 Proc. Natl. Acad. Sci. USA 89: 6599–6603.

  • Kutchera W, Jones DA, Matsunami N, Groden J, McIntyre TM, Zimmerman GA, White RL and Prescott SM. . 1996 Proc. Natl. Acad. Sci. USA 93: 4816–4820.

  • Lupu R, Cardillo M, Harris L, Hijazi M and Rosenberg K. . 1995 Cancer Biol. 6: 135–145.

  • Mandal M, Adam L, Mendelsohn J and Kumar R. . 1998 Oncogene In Press.

  • Mandal M, Wu X and Kumar R. . 1997 Carcinogenesis 18: 229–232.

    Article  CAS  Google Scholar 

  • Mandal M, Maggirwar SB, Sharma N, Kaufmann SH, Sun S and Kumar R. . 1996 J. Biol. Chem. 271: 30354–30359.

    Article  CAS  Google Scholar 

  • Martin TE, Barghusen SC, Leser GP and Spear PG. . 1987 J. Cell. Biol. 105: 2069–2082.

  • Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, Trzaskos JM, Evans JF and Taketo MM. . 1996 Cell 87: 803–809.

    Article  CAS  Google Scholar 

  • Pinkas-Kramarski R, Soussan L, Waterman H, Levkowizt G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M and Yarden Y. . 1997 EMBO J. 15: 2452–2467.

  • Pinkas-Kramarski R, Shelly M, Glathe S, Ratzkin BJ and Yarden Y. . 1996 J. Biol. Chem. 271: 19029–19032.

    Article  CAS  Google Scholar 

  • Prescott SM and White RL. . 1996 Cell 87: 783–786.

    Article  CAS  Google Scholar 

  • Rajkumar J, Goden CSR, Lemoine NR and Gullick WJ. . 1993 J. Pathol. 170: 271–278.

    Article  CAS  Google Scholar 

  • Reidel H, Massoglia S, Schlessinger J and Ullrich A. . 1988 Proc. Natl. Acad. Sci. USA 85: 1477–1481.

  • Sierke SL, Cheng K, Kim H and Koland JG. . 1997 Biochem. J. 322: 757–763.

    Article  CAS  Google Scholar 

  • Sheng H, Shao J, Kirkland SC, Isakson P, Coffey RJ, Morrow J, Beauchamp RD and DuBois RN. . 1997 J. Clin. Invest. 99: 2254–2259.

    Article  CAS  Google Scholar 

  • Smith WL, Garavito RM and DeWitt DL. . 1996 J. Biol. Chem. 271: 33157–33160.

    Article  CAS  Google Scholar 

  • Tsujii M and DuBois RN. . 1995 Cell 83: 493–501.

    Article  CAS  Google Scholar 

  • Ullrich A and Schlessinger J. . 1990 Cell 61: 203–212.

    Article  CAS  Google Scholar 

  • Untawale S, Zorbas MA, Hodgson CP, Coffey RJ, Gallick GE, North SM, Wildrick DM, Olive M, Blick M, Yeoman LC and Boman BW. . 1993 Cancer Res. 53: 1630–1636.

  • Yang J, Yu Y, Markovic B, Russell PJ and Crowe PJ. . 1997 Anticancer Res. 17: 1023–1026.

  • Wen D, Peles E, Cupples R, Suggs SF, Bacus SS, Luo Y, Trail G, Hu S, Silbiger R, Levy R, Koski RA, Lu SH and Yarden Y. . 1992 Cell 69: 559–572.

    Article  CAS  Google Scholar 

  • Zhang K, Sun J, Liu N, Wen D, Chang D, Thomason A and Yoshinaga SK. . 1996 J. Biol. Chem. 271: 3884–3890.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Steve Prescott for providing the COX-2 luciferase plasmid, MG Brattain for FET cells, and Mien-Chie Hung for NDF cDNA. This study was supported in-part by the American Institute for Cancer Research grant 96A077, the National Institute of Health grant CA65746, and new research program funds from The UTMDACC (RK).

Author information

Author notes

  1. Ratna Vadlamudi and Mahitosh Mandal: RV and MM contributed equally to this study

Authors and Affiliations

  1. Department of Clinical Investigation, Cell Growth Regulation Laboratory, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, 77030, Texas, USA

    Ratna Vadlamudi, Mahitosh Mandal, Liana Adam, John Mendelsohn & Rakesh Kumar

  2. Department of Gastrointestinal Oncology and Digestive Diseases, Cell Growth Regulation Laboratory, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, 77030, Texas, USA

    Gideon Steinbach

Authors
  1. Ratna Vadlamudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahitosh Mandal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liana Adam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gideon Steinbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John Mendelsohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rakesh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vadlamudi, R., Mandal, M., Adam, L. et al. Regulation of Cyclooxygenase-2 pathway by HER2 receptor. Oncogene 18, 305–314 (1999). https://doi.org/10.1038/sj.onc.1202307

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202307

Keywords

This article is cited by

Search

Advanced search

Quick links