beta-Adrenergic receptors in pediatric tumors: uncoupled beta 1-adrenergic receptor in Ewing's sarcoma.

Abstract

beta-Adrenergic receptors were demonstrated in membrane preparations from 6 human Ewing's sarcomas and compared to those from 46 other pediatric cancers with the use of the beta-adrenergic antagonist (-)-(3H)dihydroalprenolol [(-)[3H]DHA]. In contrast to the high numbers of receptor sites found in Ewing's sarcomas (55-640 fmol x mg-1 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 beta-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 beta 1-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 beta-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 the competition experiments with (-)-isoproterenol (in the presence or absence of guanine nucleotide) were approximately 1.0. These uncoupled receptors were resistant to N-ethylmaleimide denaturation and were densensitized only 50% during culture in the presence of (-)-isoproterenol. Thus Ewing's sarcomas are relatively rich in beta-adrenergic sites, and several tumors appear to have a coupling lesion involving guanine nucleotide-dependent regulatory protein interaction with beta-adrenergic receptors and adenylate cyclase, similar in phenotype to that described in the (unc) variant of S49 mouse lymphoma.

• Authors: J A Whitsett, J Burdsall, L Workman, B Hollinger, J Neely
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 71 Issue 4 Pg. 779-86 (Oct 1983) ISSN: 0027-8874 [Print] United States
• PMID: 6312152 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic beta-Antagonists
• Ethanolamines
• Receptors, Adrenergic, beta
• Dihydroalprenolol
• zinterol
• Adenylyl Cyclases
• Metoprolol

Topics

• Adenylyl Cyclases (metabolism)
• Adrenergic beta-Antagonists
• Animals
• Binding, Competitive
• Bone Neoplasms (metabolism)
• Cell Line
• Child
• Dihydroalprenolol (pharmacology)
• Ethanolamines (pharmacology)
• Humans
• Metoprolol (pharmacology)
• Mice
• Mice, Nude
• Neuroblastoma
• Osteosarcoma
• Receptors, Adrenergic, beta (analysis)
• Sarcoma, Ewing (metabolism)