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 cancers and is rapidly growing, widely metastatic, and rarely curable. Autocrine stimulation of multiple G protein-coupled neuropeptide receptor systems contributes to the transformed growth of SCLC. The ability of neuropeptide receptors to stimulate phospholipase C and mobilize intracellular Ca2+ indicates that Gq family members of heterotrimeric G proteins are a convergence point mediating autocrine signaling by multiple neuropeptides in SCLC. Expression of a GTPase-deficient, constitutive active form of an alpha q family member, alpha 16Q212L, in SCLC markedly inhibited growth of the cells in soft agar and tumor formation in nude mice. SCLC lines expressing alpha 16Q212L exhibited 2-4-fold elevated basal phospholipase C activity, but neuropeptide and hormone-regulated intracellular Ca2+ mobilization was nearly abolished. The data suggest that Ca2+ mobilization is an obligatory signal in neuropeptide-stimulated growth of SCLC. In addition, the proline-directed c-Jun NH2-terminal kinases/stress-activated protein kinases, which are members of the mitogen-activated protein kinase family, were stimulated approximately 2-fold in parental SCLC in response to exogenous neuropeptides and muscarinic agonists and were constitutively activated to the same degree in alpha 16Q212L-expressing SCLC. Thus, alpha 16Q212L expression induced desensitizaton of neuropeptide-stimulated Ca2+ signaling and persistent activation of the c-Jun NH2-terminal kinase/stress-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.
Department of Medicine, University of Colorado Health Sciences Center, Denver, 80262.
L E
LE
Heasley
J
J
Zamarripa
B
B
Storey
B
B
Helfrich
F M
FM
Mitchell
P A
PA
Bunn
G L
GL
Johnson
D000595:Amino Acid Sequence; D000818:Animals; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000172:deficiency*; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008969:Molecular Sequence Data; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000242:Cyclic AMP; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins