Beta-adrenoceptor signaling and its control of cell replication in MDA-MB-231 human breast cancer cells.
MDA-MB-231 human breast cancer cells express high beta-adrenoceptor levels, predominantly the beta2 subtype. Receptor stimulation by isoproterenol evoked immediate reductions in DNA synthesis which were blocked completely by propranolol and were of the same magnitude as effects elicited by high concentrations of 8-Br-cAMP. Isoproterenol-induced inhibition of DNA synthesis was maintained throughout several days of exposure, resulting in a decrement in total cell number, and the effects were augmented by cotreatment with dexamethasone; an even greater effect was seen when cAMP breakdown was inhibited by theophylline, with or without addition of isoproterenol. Despite the persistent effect of isoproterenol, receptor downregulation was evident with as little as 1 h of treatment, and over 90% of the receptors were lost within 24 h. Receptor downregulation was paralleled by homologous desensitization of the adenylyl cyclase response to beta-adrenoceptor stimulation. Dexamethasone augmented the effects of isoproterenol on DNA synthesis but did not prevent receptor downregulation or desensitization. These results indicate that beta-adrenoceptors are effectively linked, through cAMP, to the termination of cell replication in MDA-MB-231 human breast cancer cells, and that activation of only a small number of receptors is sufficient for a maximal effect. Novel pharmacologic strategies that focus on cell surface receptors operating through adenylyl cyclase may offer opportunities to combat cancers that are unresponsive to hormonal agents, or that have developed multidrug resistance.
Slotkin
T A
TA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Zhang
J
J
Dancel
R
R
Garcia
S J
SJ
Willis
C
C
Seidler
F J
FJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000704:Analysis of Variance; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000318:Adrenergic beta-Agonists; D000893:Anti-Inflammatory Agents; D018343:Receptors, Adrenergic, beta-2; D003907:Dexamethasone; D004247:DNA; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol