β-Adrenergic signalling in neoplastic lung type 2 cells: Glucocorticoid-dependent and -independent defects

Abstract

Tumorigenic mouse lung-derived type 2 cell lines have large reductions in both β-adrenergic-stimulated cAMP production and ligand binding to β-adrenergic receptors. These tumorigenic cells are also relatively insensitive to glucocorticoids. Because glucocorticoids regulate both β-adrenergic receptor expression and receptor coupling to the stimulatory guanine nucleotide binding protein G(s), interactions between the glucocorticoid and β-adrenergic signalling systems were examined. This study demonstrates that β-adrenergic ligand binding and agonist sensitivity are increased in a tumorigenic cell line stably expressing a normal glucocorticoid receptor transgene. However, although the transfected tumour cells and non-tumorigenic cells have similar amounts and affinities of β-adrenergic agonist and antagonist binding, similar amounts of G(s) subunits and similar forskolin-stimulated adenylyl cyclase activities, the former remain much less isoproterenol responsive. Competition binding studies demonstrate that tumour cell β-adrenergic receptors have both high-and low-affinity agonist binding but are functionally uncoupled from G(s). This uncoupling may involve an alteration in G(s), as guanine nucleotides exhibit a reduced ability to stimulate adenylyl cyclase. Thus, some aspects of tumorigenic cell dysfunction in β-adrenergic signalling can be ameliorated by interactions with the glucocorticoid pathway, but additional defects are also involved.