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 Article
  • Published:

A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway

Oncogene volume 26, pages 3777–3788 (2007)Cite this article

Abstract

A chemical biology approach identifies a beta 2 adrenergic receptor (β2AR) agonist ARA-211 (Pirbuterol), which causes apoptosis and human tumor regression in animal models. β2AR stimulation of cAMP formation and protein kinase A (PKA) activation leads to Raf-1 (but not B-Raf) kinase inactivation, inhibition of Mek-1 kinase and decreased phospho-extracellular signal-regulated kinase (Erk)1/2 levels. ARA-211 inhibition of the Raf/Mek/Erk1/2 pathway is mediated by PKA and not exchange protein activated by cAMP (EPAC). ARA-211 is selective and suppresses P-Erk1/2 but not P-JNK, P-p38, P-Akt or P-STAT3 levels. β2AR stimulation results in inhibition of anchorage-dependent and -independent growth, induction of apoptosis in vitro and tumor regression in vivo. β2AR antagonists and constitutively active Mek-1 rescue from the effects of ARA-211, demonstrating that β2AR stimulation and Mek kinase inhibition are required for ARA-211 antitumor activity. Furthermore, suppression of growth occurs only in human tumors where ARA-211 induces cAMP formation and decreases P-Erk1/2 levels. Thus, β2AR stimulation results in significant suppression of malignant transformation in cancers where it blocks the Raf-1/Mek-1/Erk1/2 pathway by a cAMP-dependent activation of PKA but not EPAC.

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

Similar content being viewed by others

References

  • Alvarez JV, Frank DA . (2004). Genome-wide analysis of STAT target genes: elucidating the mechanism of STAT-mediated oncogenesis. Cancer Biol Ther 3: 1045–1050.

    Article  CAS  Google Scholar 

  • Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM . (2003). Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res 63: 1270–1279.

    CAS  Google Scholar 

  • Bos JL . (1989). Ras oncogenes in human cancer: a review. Cancer Res 49: 4682–4689.

    CAS  Google Scholar 

  • Carman CV, Benovic JL . (1998). G-protein-coupled receptors: turn-ons and turn-offs. Curr Opin Neurobiol 8: 335–344.

    Article  CAS  Google Scholar 

  • Cox ME, Deeble PM, Bissonette EA, Parsons SJ . (2000). Activated 3′,5′-cyclic AMP-dependent protein kinase is sufficient to induce neuroendocrine-like differentiation of the LNCaP prostate tumor cell line. J Biol Chem 275: 13812–13818.

    Article  CAS  Google Scholar 

  • Dhillon AS, Kolch W . (2002). Untying the regulation of the Raf-1 kinase. Arch Biochem Biophys 404: 3–9.

    Article  CAS  Google Scholar 

  • Di Marco E, Pierce JH, Fleming TP, Kraus MH, Molloy CJ, Aaronson SA et al. (1989). Autocrine interaction between TGF alpha and the EGF-receptor: quantitative requirements for induction of the malignant phenotype. Oncogene 4: 831–838.

    CAS  PubMed  Google Scholar 

  • Dumaz N, Marais R . (2005). Integrating signals between cAMP and the RAS/RAF/MEK/ERK signalling pathways. Based on the anniversary prize of the Gesellschaft fur Biochemie und Molekularbiologie Lecture delivered on 5 July 2003 at the Special FEBS Meeting in Brussels. FEBS J 272: 3491–3504.

    Article  CAS  Google Scholar 

  • English JM, Cobb MH . (2002). Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci 23: 40–45.

    Article  CAS  Google Scholar 

  • Enserink JM, Christensen AE, de Rooij J, van Triest M, Schwede F, Genieser HG et al. (2002). A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nat Cell Biol 4: 901–906.

    Article  CAS  Google Scholar 

  • Erhardt P, Troppmair J, Rapp UR, Cooper GM . (1995). Differential regulation of Raf-1 and B-Raf and Ras-dependent activation of mitogen-activated protein kinase by cyclic AMP in PC12 cells. Mol Cell Biol 15: 5524–5530.

    Article  CAS  Google Scholar 

  • Fleming TP, Matsui T, Aaronson SA . (1992). Platelet-derived growth factor (PDGF) receptor activation in cell transformation and human malignancy. Exp Gerontol 27: 523–532.

    Article  CAS  Google Scholar 

  • Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M . (2004). PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30: 193–204.

    Article  Google Scholar 

  • Graells J, Vinyals A, Figueras A, Llorens A, Moreno A, Marcoval J et al. (2004). Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling. J Invest Dermatol 123: 1151–1161.

    Article  CAS  Google Scholar 

  • Grassi V, Daniotti S, Schiassi M, Dottorini M, Tantucci C . (1986). Oral beta 2-selective adrenergic bronchodilators. Int J Clin Pharmacol Res 6: 93–103.

    CAS  PubMed  Google Scholar 

  • Graves LM, Bornfeldt KE, Raines EW, Potts BC, Macdonald SG, Ross R et al. (1993). Protein kinase A antagonizes platelet-derived growth factor-induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells. Proc Natl Acad Sci USA 90: 10300–10304.

    Article  CAS  Google Scholar 

  • Hafner S, Adler HS, Mischak H, Janosch P, Heidecker G, Wolfman A et al. (1994). Mechanism of inhibition of Raf-1 by protein kinase A. Mol Cell Biol 14: 6696–6703.

    Article  CAS  Google Scholar 

  • Hagemann C, Blank JL . (2001). The ups and downs of MEK kinase interactions. Cell Signal 13: 863–875.

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  Google Scholar 

  • Hao D, Rowinsky EK . (2002). Inhibiting signal transduction: recent advances in the development of receptor tyrosine kinase and Ras inhibitors. Cancer Invest 20: 387–404.

    Article  CAS  Google Scholar 

  • Jiang Z, Wu CL, Woda BA, Iczkowski KA, Chu PG, Tretiakova MS et al. (2004). Alpha-methylacyl-CoA racemase: a multi-institutional study of a new prostate cancer marker. Histopathology 45: 218–225.

    Article  CAS  Google Scholar 

  • Jin W, Wu L, Liang K, Liu B, Lu Y, Fan Z . (2003). Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells. Br J Cancer 89: 185–191.

    Article  CAS  Google Scholar 

  • Johnson GL, Lapadat R . (2002). Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298: 1911–1912.

    Article  CAS  Google Scholar 

  • Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J et al. (2005). Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res 11: 6414–6421.

    Article  CAS  Google Scholar 

  • Lerner EC, Zhang TT, Knowles DB, Qian Y, Hamilton AD, Sebti SM . (1997). Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 15: 1283–1288.

    Article  CAS  Google Scholar 

  • Maudsley S, Pierce KL, Zamah AM, Miller WE, Ahn S, Daaka Y et al. (2000). The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor. J Biol Chem 275: 9572–9580.

    Article  CAS  Google Scholar 

  • Moore PF, Constantine JW, Barth WE . (1978). Pirbuterol, a selective beta2 adrenergic bronchodilator. J Pharmacol Exp Ther 207: 410–418.

    CAS  PubMed  Google Scholar 

  • Redell MS, Tweardy DJ . (2005). Targeting transcription factors for cancer therapy. Curr Pharm Des 11: 2873–2887.

    Article  CAS  Google Scholar 

  • Schmitt JM, Stork PJ . (2001). Cyclic AMP-mediated inhibition of cell growth requires the small G protein Rap1. Mol Cell Biol 21: 3671–3683.

    Article  CAS  Google Scholar 

  • Schmitt JM, Stork PJ . (2002). PKA phosphorylation of Src mediates cAMP's inhibition of cell growth via Rap1. Mol Cell 9: 85–94.

    Article  CAS  Google Scholar 

  • Sebolt-Leopold JS . (2000). Development of anticancer drugs targeting the MAP kinase pathway. Oncogene 19: 6594–6599.

    Article  CAS  Google Scholar 

  • Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC et al. (1999). Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 5: 810–816.

    Article  CAS  Google Scholar 

  • Sebti SM, Tkalcevic GT, Jani JP . (1991). Lovastatin, a cholesterol biosynthesis inhibitor, inhibits the growth of human H-ras oncogene transformed cells in nude mice. Cancer Commun 3: 141–147.

    Article  CAS  Google Scholar 

  • Sevetson BR, Kong X, Lawrence Jr JC . (1993). Increasing cAMP attenuates activation of mitogen-activated protein kinase. Proc Natl Acad Sci USA 90: 10305–10309.

    Article  CAS  Google Scholar 

  • Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL . (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182.

    Article  CAS  Google Scholar 

  • Slotkin TA, Seidler FJ . (2000). Antimitotic and cytotoxic effects of theophylline in MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat 64: 259–267.

    Article  CAS  Google Scholar 

  • Slotkin TA, Zhang J, Dancel R, Garcia SJ, Willis C, Seidler FJ . (2000). Beta-adrenoceptor signaling and its control of cell replication in MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat 60: 153–166.

    Article  CAS  Google Scholar 

  • Steen SN, Ziment I, Thomas JS . (1974). Pyrbuterol: a new bronchodilator. Phase I-single dose study. Curr Ther Res Clin Exp 16: 1077–1081.

    CAS  PubMed  Google Scholar 

  • Steinberg SF . (2000). The cellular actions of beta-adrenergic receptor agonists: looking beyond cAMP. Circ Res 87: 1079–1082.

    Article  CAS  Google Scholar 

  • Stork PJ, Schmitt JM . (2002). Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 12: 258–266.

    Article  CAS  Google Scholar 

  • Strobl JS, Wonderlin WF, Flynn DC . (1995). Mitogenic signal transduction in human breast cancer cells. Gen Pharmacol 26: 1643–1649.

    Article  CAS  Google Scholar 

  • Sun J, Ohkanda J, Coppola D, Yin H, Kothare M, Busciglio B et al. (2003). Geranylgeranyltransferase I inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice. Cancer Res 63: 8922–8929.

    CAS  PubMed  Google Scholar 

  • Sun J, Wang DA, Jain RK, Carie A, Paquette S, Ennis E et al. (2005). Inhibiting angiogenesis and tumorigenesis by a synthetic molecule that blocks binding of both VEGF and PDGF to their receptors. Oncogene 24: 4701–4709.

    Article  CAS  Google Scholar 

  • Tortora G, Ciardiello F . (2002). Protein kinase A as target for novel integrated strategies of cancer therapy. Ann NY Acad Sci 968: 139–147.

    Article  CAS  Google Scholar 

  • Troadec JD, Marien M, Mourlevat S, Debeir T, Ruberg M, Colpaert F et al. (2002). Activation of the mitogen-activated protein kinase (ERK(1/2)) signaling pathway by cyclic AMP potentiates the neuroprotective effect of the neurotransmitter noradrenaline on dopaminergic neurons. Mol Pharmacol 62: 1043–1052.

    Article  CAS  Google Scholar 

  • Veber N, Prevost G, Planchon P, Starzec A . (1994). Evidence for a growth effect of epidermal growth factor on MDA-MB-231 breast cancer cells. Eur J Cancer 30A: 1352–1359.

    Article  CAS  Google Scholar 

  • Vossler MR, Yao H, York RD, Pan MG, Rim CS, Stork PJ . (1997). cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89: 73–82.

    Article  CAS  Google Scholar 

  • Watanabe M, Nobuta A, Tanaka J, Asaka M . (1996). An effect of K-ras gene mutation on epidermal growth factor receptor signal transduction in PANC-1 pancreatic carcinoma cells. Int J Cancer 67: 264–268.

    Article  CAS  Google Scholar 

  • Weinstein-Oppenheimer CR, Blalock WL, Steelman LS, Chang F, McCubrey JA . (2000). The Raf signal transduction cascade as a target for chemotherapeutic intervention in growth factor-responsive tumors. Pharmacol Ther 88: 229–279.

    Article  CAS  Google Scholar 

  • Weldon CB, Scandurro AB, Rolfe KW, Clayton JL, Elliott S, Butler NN . (2002). Identification of mitogen-activated protein kinase kinase as a chemoresistant pathway in MCF-7 cells by using gene expression microarray. Surgery 132: 293–301.

    Article  Google Scholar 

  • Wu J, Dent P, Jelinek T, Wolfman A, Weber MJ, Sturgill TW . (1993). Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3′,5′-monophosphate. Science 262: 1065–1069.

    Article  CAS  Google Scholar 

  • Yu M, Sato H, Seiki M, Spiegel S, Thompson EW . (1998). Elevated cyclic AMP suppresses ConA-induced MT1-MMP expression in MDA-MB-231 human breast cancer cells. Clin Exp Metastasis 16: 185–191.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ms Hong Chen and Mr Adrian Kenney for their technical assistance. This work has been supported in part by the Pathology Core Facility, Histology Laboratory, Analytical Microscopy Core Facility and Molecular Imaging Core Facility at the University of South Florida College of Medicine and at H Lee Moffitt Cancer Center & Research Institute.

Author information

Authors and Affiliations

  1. Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA

    A E Carie & S M Sebti

  2. Department of Interdisciplinary Oncology, University of South Florida, Tampa, FL, USA

    A E Carie & S M Sebti

Authors
  1. A E Carie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S M Sebti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S M Sebti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carie, A., Sebti, S. A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway. Oncogene 26, 3777–3788 (2007). https://doi.org/10.1038/sj.onc.1210172

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210172

Keywords

This article is cited by

Search

Advanced search

Quick links