Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2003 Apr 15;371(Pt 2):581–587. doi: 10.1042/BJ20021708

Requirement for direct cross-talk between B1 and B2 kinin receptors for the proliferation of androgen-insensitive prostate cancer PC3 cells.

Liza Barki-Harrington 1, Angela L Bookout 1, Gaofeng Wang 1, Maria E Lamb 1, L M Fredrik Leeb-Lundberg 1, Yehia Daaka 1
PMCID: PMC1223306  PMID: 12534343

Abstract

Stimulation of endogenous kinin receptors promotes growth of androgen-independent prostate cancer PC3 cells via activation of the mitogenic extracellular-signal-regulated kinase (ERK) pathway. In the present study, we show that kinin-mediated mitogenic signalling and prostate-cell growth involves two subtypes of bradykinin (BK) receptors, B1R and B2R. Specific stimulation of either B1R or B2R by their respective agonists des-Arg(9)-BK and Lys-BK promoted ERK activation and cell growth, whereas selective blockade with specific antagonists des-Arg(9)-[Leu(8)]BK and Hoe 140 respectively obliterated this effect, indicating the presence of both receptor subtypes. However, blockade of B1R also inhibited B2R-mediated ERK activation and cell growth, and, similarly, antagonism of B2R inhibited the B1R-mediated response. Furthermore, both B1R and B2R agonists promoted internalization of B1R, whereas both receptor antagonists blocked this effect. The B1R ligands des-Arg(9)-BK and des-Arg(9)-[Leu(8)]BK had no effect on the binding of BK to B2R, as demonstrated by radioligand competitive binding studies. However, blockade of either B1R or B2R impaired the ability of the reciprocal receptor to produce inositol phosphates, suggesting that the interaction between B1R and B2R is proximal to activation of phospholipase C. These results provide evidence for the existence of B1R-B2R complexes in prostate cancer PC3 cells and demonstrate that antagonism of one receptor interferes with the signalling ability of the other, possibly at the level of receptor-Galpha(q) protein coupling. Selective inhibition of B1R, which is up-regulated in injured and cancerous tissue, may be beneficial for the treatment of advanced prostate cancer.

Full Text

The Full Text of this article is available as a PDF (177.9 KB).

Selected References

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

  1. Abate-Shen C., Shen M. M. Molecular genetics of prostate cancer. Genes Dev. 2000 Oct 1;14(19):2410–2434. doi: 10.1101/gad.819500. [DOI] [PubMed] [Google Scholar]
  2. AbdAlla S., Lother H., Quitterer U. AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature. 2000 Sep 7;407(6800):94–98. doi: 10.1038/35024095. [DOI] [PubMed] [Google Scholar]
  3. AbdAlla S., Lother H., el Massiery A., Quitterer U. Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nat Med. 2001 Sep;7(9):1003–1009. doi: 10.1038/nm0901-1003. [DOI] [PubMed] [Google Scholar]
  4. Barki-Harrington L., Daaka Y. Bradykinin induced mitogenesis of androgen independent prostate cancer cells. J Urol. 2001 Jun;165(6 Pt 1):2121–2125. doi: 10.1097/00005392-200106000-00081. [DOI] [PubMed] [Google Scholar]
  5. Bouvier M. Oligomerization of G-protein-coupled transmitter receptors. Nat Rev Neurosci. 2001 Apr;2(4):274–286. doi: 10.1038/35067575. [DOI] [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  7. Charlesworth M. C., Young C. Y., Miller V. M., Tindall D. J. Kininogenase activity of prostate-derived human glandular kallikrein (hK2) purified from seminal fluid. J Androl. 1999 Mar-Apr;20(2):220–229. [PubMed] [Google Scholar]
  8. Daaka Y., Luttrell L. M., Ahn S., Della Rocca G. J., Ferguson S. S., Caron M. G., Lefkowitz R. J. Essential role for G protein-coupled receptor endocytosis in the activation of mitogen-activated protein kinase. J Biol Chem. 1998 Jan 9;273(2):685–688. doi: 10.1074/jbc.273.2.685. [DOI] [PubMed] [Google Scholar]
  9. Devi L. A. Heterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking. Trends Pharmacol Sci. 2001 Oct;22(10):532–537. doi: 10.1016/s0165-6147(00)01799-5. [DOI] [PubMed] [Google Scholar]
  10. Djakiew D. Dysregulated expression of growth factors and their receptors in the development of prostate cancer. Prostate. 2000 Feb 1;42(2):150–160. doi: 10.1002/(sici)1097-0045(20000201)42:2<150::aid-pros10>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  11. Faas F. H., Dang A. Q., White J., Schaefer R., Johnson D. Increased prostatic lysophosphatidylcholine acyltransferase activity in human prostate cancer: a marker for malignancy. J Urol. 2001 Feb;165(2):463–468. doi: 10.1097/00005392-200102000-00026. [DOI] [PubMed] [Google Scholar]
  12. Ferguson S. S. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev. 2001 Mar;53(1):1–24. [PubMed] [Google Scholar]
  13. Finlay J. A., Evans C. L., Day J. R., Payne J. K., Mikolajczyk S. D., Millar L. S., Kuus-Reichel K., Wolfert R. L., Rittenhouse H. G. Development of monoclonal antibodies specific for human glandular kallikrein (hK2): development of a dual antibody immunoassay for hK2 with negligible prostate-specific antigen cross-reactivity. Urology. 1998 May;51(5):804–809. doi: 10.1016/s0090-4295(98)00107-1. [DOI] [PubMed] [Google Scholar]
  14. Gioeli D., Mandell J. W., Petroni G. R., Frierson H. F., Jr, Weber M. J. Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res. 1999 Jan 15;59(2):279–284. [PubMed] [Google Scholar]
  15. Gohji K., Kitazawa S., Tamada H., Katsuoka Y., Nakajima M. Expression of endothelin receptor a associated with prostate cancer progression. J Urol. 2001 Mar;165(3):1033–1036. [PubMed] [Google Scholar]
  16. Guo C., Luttrell L. M., Price D. T. Mitogenic signaling in androgen sensitive and insensitive prostate cancer cell lines. J Urol. 2000 Mar;163(3):1027–1032. [PubMed] [Google Scholar]
  17. Haese A., Graefen M., Steuber T., Becker C., Pettersson K., Piironen T., Noldus J., Huland H., Lilja H. Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ-confined from locally-advanced prostate cancer in total PSA-levels below 10 ng/ml. Prostate. 2001 Oct 1;49(2):101–109. doi: 10.1002/pros.1123. [DOI] [PubMed] [Google Scholar]
  18. Hall J. M. Bradykinin receptors. Gen Pharmacol. 1997 Jan;28(1):1–6. doi: 10.1016/s0306-3623(96)00174-7. [DOI] [PubMed] [Google Scholar]
  19. Hamm H. E. How activated receptors couple to G proteins. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):4819–4821. doi: 10.1073/pnas.011099798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jemal Ahmedin, Thomas Andrea, Murray Taylor, Thun Michael. Cancer statistics, 2002. CA Cancer J Clin. 2002 Jan-Feb;52(1):23–47. doi: 10.3322/canjclin.52.1.23. [DOI] [PubMed] [Google Scholar]
  21. Jordan B. A., Devi L. A. G-protein-coupled receptor heterodimerization modulates receptor function. Nature. 1999 Jun 17;399(6737):697–700. doi: 10.1038/21441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jordan B. A., Trapaidze N., Gomes I., Nivarthi R., Devi L. A. Oligomerization of opioid receptors with beta 2-adrenergic receptors: a role in trafficking and mitogen-activated protein kinase activation. Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):343–348. doi: 10.1073/pnas.011384898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kue P. F., Daaka Y. Essential role for G proteins in prostate cancer cell growth and signaling. J Urol. 2000 Dec;164(6):2162–2167. [PubMed] [Google Scholar]
  24. Lefkowitz Robert J., Pierce Kristen L., Luttrell Louis M. Dancing with different partners: protein kinase a phosphorylation of seven membrane-spanning receptors regulates their G protein-coupling specificity. Mol Pharmacol. 2002 Nov;62(5):971–974. doi: 10.1124/mol.62.5.971. [DOI] [PubMed] [Google Scholar]
  25. Lin F. T., Krueger K. M., Kendall H. E., Daaka Y., Fredericks Z. L., Pitcher J. A., Lefkowitz R. J. Clathrin-mediated endocytosis of the beta-adrenergic receptor is regulated by phosphorylation/dephosphorylation of beta-arrestin1. J Biol Chem. 1997 Dec 5;272(49):31051–31057. doi: 10.1074/jbc.272.49.31051. [DOI] [PubMed] [Google Scholar]
  26. Noel J. P., Hamm H. E., Sigler P. B. The 2.2 A crystal structure of transducin-alpha complexed with GTP gamma S. Nature. 1993 Dec 16;366(6456):654–663. doi: 10.1038/366654a0. [DOI] [PubMed] [Google Scholar]
  27. Parent J. L., Labrecque P., Orsini M. J., Benovic J. L. Internalization of the TXA2 receptor alpha and beta isoforms. Role of the differentially spliced cooh terminus in agonist-promoted receptor internalization. J Biol Chem. 1999 Mar 26;274(13):8941–8948. doi: 10.1074/jbc.274.13.8941. [DOI] [PubMed] [Google Scholar]
  28. Phagoo S. B., Reddi K., Anderson K. D., Leeb-Lundberg L. M., Warburton D. Bradykinin B1 receptor up-regulation by interleukin-1beta and B1 agonist occurs through independent and synergistic intracellular signaling mechanisms in human lung fibroblasts. J Pharmacol Exp Ther. 2001 Jul;298(1):77–85. [PubMed] [Google Scholar]
  29. Pizard A., Marchetti J., Allegrini J., Alhenc-Gelas F., Rajerison R. M. Negative cooperativity in the human bradykinin B2 receptor. J Biol Chem. 1998 Jan 16;273(3):1309–1315. doi: 10.1074/jbc.273.3.1309. [DOI] [PubMed] [Google Scholar]
  30. Price D. T., Della Rocca G., Guo C., Ballo M. S., Schwinn D. A., Luttrell L. M. Activation of extracellular signal-regulated kinase in human prostate cancer. J Urol. 1999 Oct;162(4):1537–1542. [PubMed] [Google Scholar]
  31. Raj Ganesh V., Barki-Harrington Liza, Kue Pao F., Daaka Yehia. Guanosine phosphate binding protein coupled receptors in prostate cancer: a review. J Urol. 2002 Mar;167(3):1458–1463. [PubMed] [Google Scholar]
  32. Rocheville M., Lange D. C., Kumar U., Sasi R., Patel R. C., Patel Y. C. Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. J Biol Chem. 2000 Mar 17;275(11):7862–7869. doi: 10.1074/jbc.275.11.7862. [DOI] [PubMed] [Google Scholar]
  33. Sawant S., Snyman C., Bhoola K. Comparison of tissue kallikrein and kinin receptor expression in gastric ulcers and neoplasms. Int Immunopharmacol. 2001 Nov;1(12):2063–2080. doi: 10.1016/s1567-5769(01)00118-7. [DOI] [PubMed] [Google Scholar]
  34. Xu L. L., Stackhouse B. G., Florence K., Zhang W., Shanmugam N., Sesterhenn I. A., Zou Z., Srikantan V., Augustus M., Roschke V. PSGR, a novel prostate-specific gene with homology to a G protein-coupled receptor, is overexpressed in prostate cancer. Cancer Res. 2000 Dec 1;60(23):6568–6572. [PubMed] [Google Scholar]
  35. Yang C. M., Tsai Y. J., Pan S. L., Lin C. C., Wu W. B., Wang C. C., Huang S. C., Chiu C. T. Inhibition of bradykinin-induced phosphoinositide hydrolysis and Ca2+ mobilisation by phorbol ester in rat cultured vascular smooth muscle cells. Cell Signal. 1999 Dec;11(12):899–907. doi: 10.1016/s0898-6568(99)00061-3. [DOI] [PubMed] [Google Scholar]
  36. Zhao X. Y., Malloy P. J., Krishnan A. V., Swami S., Navone N. M., Peehl D. M., Feldman D. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med. 2000 Jun;6(6):703–706. doi: 10.1038/76287. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES