DISCORDANT SIGNAL-TRANSDUCTION AND GROWTH-INHIBITION OF SMALL-CELL LUNG CARCINOMAS INDUCED BY EXPRESSION OF GTPASE-DEFICIENT G-ALPHA(16)

Small cell lung carcinoma (SCLC) accounts for 20-25% of primary lung c ancers and is rapidly growing, widely metastatic, and rarely curable, Autocrine stimulation of multiple G protein-coupled neuropeptide recep tor systems contributes to the transformed growth of SCLC, The ability of neuropeptide receptors to stimulate phospholipase C and mobilize i ntracellular Ca2+ indicates that G(q) family members of heterotrimeric G proteins are a convergence point mediating autocrine signaling by m ultiple neuropeptides in SCLC, Expression of a GTPase-deficient, const itutive active form of an alpha(q) family member, alpha(16)Q212L, in S CLC markedly inhibited growth of the cells in soft agar and tumor form ation in nude mice, SCLC lines expressing alpha(16)Q212L exhibited 2-4 -fold elevated basal phospholipase C activity, but neuropeptide and ho rmone-regulated intracellular Ca2+ mobilization was nearly abolished, The data suggest that Ca2+ mobilization is an obligatory signal in neu ropeptide-stimulated growth of SCLC, In addition, the proline-directed c-Jun NH2-terminal kinases/stress-activated protein kinases, which ar e members of the mitogen-activated protein kinase family, were stimula ted similar to-2-fold in parental SCLC in response to exogenous neurop eptides and muscarinic agonists and were constitutively activated to t he same degree in alpha(16)Q212L-expressing SCLC, Thus, alpha(16)Q212L expression induced desensitization of neuropeptide stimulated Ca2+ si gnaling and persistent activation of the c-Jun NH2-terminal kinase/str ess-activated protein kinase pathway, We propose that the induction of discordant signaling by selective perturbation of receptor-regulated effector systems leads to the inhibition of SCLC cell growth.