β-Adrenergic Receptors in Pediatric Tumors: Uncoupled β1-Adrenergic Receptor in Ewing's Sarcoma

Jeffrey A. Whitsett, Jeffrey Burdsall, Linda Workman, Bryan Hollinger, John Neely

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

β-Adrenergic receptors were demonstrated in membrane preparations from 6 human Ewing's sarcomas and compared to thCJse from 46 other pediatric cancers with the use of the β-adrenergic antagonist (-)-[3H]dihydroalprenolol [(-)-[3H]DHA]. In contrast to the high numbers of receptor sites found in Ewing's sarcomas (55-640 fmol mg-' protein; dissociation constant Kd, 1–2 nM), other childhood cancers (neuroblastoma, rhabdomyosarcoma, brain tumors, lymphoma, osteosarcoma, hepatoblastoma, yolk sac, and Wilms' tumor) contained in general fewer β-adrenergic receptor sites. Characteristics of (-)-[3H]DHA binding were therefore more fully characterized in the Ewing's tumors. Competition of (-)-[3H]DHA binding by classical catecholamine agonists, as well as by subtype selective agents metoprolol and zinterol, demonstrated the presence of a homogeneous population of β,-adrenergic sites in several Ewing's tumors. Adenylate cyclase activity in all Ewing's sarcomas was enhanced by GTP and NaF. However, in spite of high numbers of β-adrenergic receptors, (-)-isoproterenol was not very effective in the activation of adenylate cyclase activity in several of the Ewing's tumors tested. Neither guanyl-5'-yl-imidophosphate nor GTP altered agonist potency for the receptor site in these catecholamine-insensitive tumors. Hill coefficients obtained from competition experiments with (-)isoproterenol (in the presence or absence of guanine nucleotide) were approximately 1.0. These uncoupled receptors were resistant to Nethylmaleimide denaturation and were densensitized only 50% during culture in the presence of (-)-isoproterenol. Thus Ewing's sarcomas are relatively rich in β-adrenergic sites, and several tumors appear to have a coupling lesion involving guanine nucleotide-dependent regulatory protein interaction with β-adrenergic receptors and adenylate cyclase, similar in phenotype to that described in the (unc) variant of S49 mouse lymphoma.

Original languageEnglish (US)
Pages (from-to)779-786
Number of pages8
JournalJournal of the National Cancer Institute
Volume71
Issue number4
DOIs
StatePublished - Oct 1983

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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