Discordant signal transduction and growth inhibition of small cell lung carcinomas induced by expression of GTPase-deficient G alpha(16)
Discordant signal transduction and growth inhibition of small cell lung carcinomas induced by expression of GTPase-deficient G alpha(16)
复制标题
DOI：
10.1074/jbc.271.1.349
复制
发表时间：
1996-01-05
影响因子：
4.8
通讯作者：
Johnson, GL
中科院分区：
文献类型：
--
作者：
Heasley, LE;Zamarripa, J;Johnson, GL
小细胞肺癌 (SCLC) 占原发性肺癌的 20-25%，生长迅速、广泛转移且很少可治愈，多种 G 蛋白偶联神经肽受体系统的自分泌刺激有助于 SCLC 的转化生长，神经肽受体刺激磷脂酶 C 和动员细胞内 Ca2+ 的能力表明异源三聚体 G 蛋白的 G(q) 家族成员是介导多种自分泌信号传导的汇聚点SCLC 中神经肽，α(q) 家族成员的 GTPase 缺陷型组成型活性形式 α(16)Q212L 在 SCLC 中的表达显着抑制软琼脂中细胞的生长和裸鼠肿瘤形成，表达 α(16)Q212L 的 SCLC 系表现出 2-4 倍的基础磷脂酶 C 活性升高，但神经肽和激素调节的细胞内 Ca2+动员几乎被废除，数据表明，Ca2+动员是神经肽刺激的 SCLC 生长中的必然信号，此外，脯氨酸导向的 c-Jun NH2 末端激酶/应激激活蛋白激酶（属于丝裂原激活蛋白激酶家族的成员）在亲本 SCLC 中受到与外源神经肽和毒蕈碱激动剂的反应类似的 2 倍刺激，并且被在表达 α(16)Q212L 的 SCLC 中组成型激活至相同程度，因此，α(16)Q212L 表达诱导神经肽刺激的 Ca2+ 信号传导脱敏，并持续激活 c-Jun NH2 末端激酶/应激激活蛋白激酶途径。我们提出，通过选择性扰动受体调节效应系统来诱导不一致的信号传导，从而抑制 SCLC 细胞生长。
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 G(q) 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(16)Q212L, in SCLC markedly inhibited growth of the cells in soft agar and tumor formation in nude mice, SCLC lines expressing alpha(16)Q212L 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 similar to-2-fold in parental SCLC in response to exogenous neuropeptides and muscarinic agonists and were constitutively activated to the same degree in alpha(16)Q212L-expressing SCLC, Thus, alpha(16)Q212L expression induced desensitization 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.