The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지

Tyrphostin ErbB2 Inhibitors AG825 and AG879 Have Non-specific Suppressive Effects on gp130/ STAT3 Signaling

  • Lee, Hyun-Kyoung (Department of Physiology, Medical Science Research Institute, College of Medicine, Dong-A University) ;
  • Seo, In-Ae (Department of Physiology, Medical Science Research Institute, College of Medicine, Dong-A University) ;
  • Lee, Sang-Hwa (Department of Microbiology, Medical Science Research Institute, College of Medicine, Dong-A University) ;
  • Seo, Su-Young (Department of Microbiology, Medical Science Research Institute, College of Medicine, Dong-A University) ;
  • Kim, Kyung-Sup (Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine) ;
  • Park, Hwan-Tae (Department of Physiology, Medical Science Research Institute, College of Medicine, Dong-A University)
  • Published : 2008.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Although the interaction between gp130 and the ErbB family has frequently been shown in cancer cells, the mechanism of this interaction remains unclear and controversial. In the present study, we found that specific tyrphostin inhibitors of ErbB2 (AG825 and AG879), but not ErbB1 inhibitor (AG1478), suppressed IL-6-induced tyrosine phosphorylation of STAT3 in schwannoma cells. However, biochemical evidence for transactivation of ErbB2 by IL-6 was not observed. Additionally, the inhibition of ErbB2 expression, with either a specific RNAi or transfection of an ErbB2 mutant lacking the intracellular domain did not inhibit the IL-6-induced tyrosine phosphorylation of STAT3. Thus, it seems that tyrphostins, which are known as specific inhibitors of the ErbB2 kinase, may have non-specific suppressive effects on the IL-6/STAT3 pathway.

Keywords

References

  1. Badache A, Hynes NE. Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Res 61: 383-391, 2001
  2. Battle TE, Frank DA. The role of STATs in apoptosis. Curr Mol Med 2: 381-392, 2002 https://doi.org/10.2174/1566524023362456
  3. Carroll SL, Miller ML, Frohnert PW, Kim SS, Corbett JA. Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J Neurosci 17: 1642-1659, 1997 https://doi.org/10.1523/JNEUROSCI.17-05-01642.1997
  4. Chan KS, Sano S, Kiguchi K, Anders J, Komazawa N, Takeda J, DiGiovanni J. Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest 114: 720-728, 2004 https://doi.org/10.1172/JCI200421032
  5. Chen ZL, Yu WM, Strickland S. Peripheral regeneration. Annu Rev Neurosci 30: 209-233, 2007 https://doi.org/10.1146/annurev.neuro.30.051606.094337
  6. Cheng L, Esch FS, Marchionni MA, Mudge AW. Control of Schwann cell survival and proliferation: autocrine factors and neuregulins. Mol Cell Neurosci 12: 141-156, 1998 https://doi.org/10.1006/mcne.1998.0706
  7. Choi BH, Choi JS, Rhie DJ, Yoon SH, Min DS, Jo YH, Kim MS, Hahn SJ. Direct inhibition of the cloned Kv1.5 channel by AG-1478, a tyrosine kinase inhibitor. Am J Physiol Cell Physiol 282: 1461-1468, 2002 https://doi.org/10.1152/ajpcell.00398.2001
  8. Gazit A, Osherov N, Posner I, Yaish P, Poradosu E, Gilon C, Levitzki A. Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. J Med Chem 34: 1896-1907, 1991 https://doi.org/10.1021/jm00110a022
  9. Grant SL, Hammacher A, Douglas AM, Goss GA, Mansfield RK, Heath JK, Begley CG. An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. Oncogene 21: 460-474, 2002 https://doi.org/10.1038/sj.onc.1205100
  10. Grunt TW, Tomek K, Wagner R, Puckmair K, Kainz B, Rünzler D, Gaiger A, Köhler G, Zielinski CC. Upregulation of retinoic acid receptor-beta by the epidermal growth factor-receptor inhibitor PD153035 is not mediated by blockade of ErbB pathways. J Cell Physiol 211: 803-815, 2007 https://doi.org/10.1002/jcp.20990
  11. Huijbregts RP, Roth KA, Schmidt RE, Carroll SL. Hypertrophic neuropathies and malignant peripheral nerve sheath tumors in transgenic mice overexpressing glial growth factor beta3 in myelinating Schwann cells. J Neurosci 23: 7269-7280, 2003 https://doi.org/10.1523/JNEUROSCI.23-19-07269.2003
  12. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5: 341-354, 2005 https://doi.org/10.1038/nrc1609
  13. Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, Hess K, Conrad C, Madden T, Sawaya R, Kondo S, Priebe W, Kondo Y. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene 26: 2435-2444, 2007 https://doi.org/10.1038/sj.onc.1210031
  14. Kamimura D, Ishihara K, Hirano T. IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol 149: 1-38, 2003
  15. Lee HK, Seo IA, Park HK, Park HT. Identification of the basement membrane protein nidogen as a candidate ligand for tumor endothelial marker 7 in vitro and in vivo. FEBS Lett 580: 2253- 2257, 2006 https://doi.org/10.1016/j.febslet.2006.03.033
  16. Lee HK, Seo IA, Park HK, Park YM, Ahn KJ, Yoo YH, Park HT. Nidogen is a prosurvival and promigratory factor for adult Schwann cells. J Neurochem 102: 686-698, 2007 https://doi.org/10.1111/j.1471-4159.2007.04580.x
  17. Lee HK, Seo IA, Seo E, Seo SY, Lee HJ, Park HT. Netrin-1 induces proliferation of Schwann cells through Unc5b receptor. Biochem Biophys Res Commun 362: 1057-1062, 2007 https://doi.org/10.1016/j.bbrc.2007.08.143
  18. Ng YP. Cheung ZH, Ip NY. STAT3 as a downstream mediator of Trk signaling and functions. J Biol Chem 281: 15636-15644, 2006 https://doi.org/10.1074/jbc.M601863200
  19. Osherov N, Gazit A, Gilon C, Levitzki A. Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins. J Biol Chem 268: 11134-11142, 1993
  20. Qiu Y, Ravi L, Kung HJ. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature 393: 83-85, 1998 https://doi.org/10.1038/30012
  21. Rahaman SO, Harbor PC, Chernova O, Barnett GH, Vogelbaum MA, Haque SJ. Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene 21: 8404-8413, 2002 https://doi.org/10.1038/sj.onc.1206047
  22. Selander KS, Li L, Watson L, Merrell M, Dahmen H, Heinrich PC, Müller-Newen G, Harris KW. Inhibition of gp130 signaling in breast cancer blocks constitutive activation of Stat3 and inhibits in vivo malignancy. Cancer Res 64: 6924-6933, 2004 https://doi.org/10.1158/0008-5472.CAN-03-2516
  23. Stonecypher MS, Byer SJ, Grizzle WE, Carroll SL. Activation of the neuregulin-1/ErbB signaling pathway promotes the proliferation of neoplastic Schwann cells in human malignant peripheral nerve sheath tumors. Oncogene 24: 5589-5605, 2005 https://doi.org/10.1038/sj.onc.1208730
  24. Tsai CM, Levitzki A, Wu LH, Chang KT, Cheng CC, Gazit A, Perng RP. Enhancement of chemosensitivity by tyrphostin AG825 in high-p185 (neu) expressing non-small cell lung cancer cells. Cancer Res 56: 1068-1074, 1996
  25. Xie Y, Tisi MA, Yeo TT, Longo FM. Nerve growth factor (NGF) loop 4 dimeric mimetics activate ERK and AKT and promote NGF-like neurotrophic effects. J Biol Chem 275: 29868-29874, 2000 https://doi.org/10.1074/jbc.M005071200