Cross talk between the bombesin neuropeptide receptor and Sonic hedgehog pathways in small cell lung carcinoma.
Cross talk between the bombesin neuropeptide receptor and Sonic hedgehog pathways in small cell lung carcinoma.
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DOI：
10.1038/onc.2014.104
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发表时间：
2015-03-26
期刊：
影响因子：
8
通讯作者：
Gutkind JS
中科院分区：
文献类型：
--
作者：
Castellone MD;Laukkanen MO;Teramoto H;Bellelli R;Alì G;Fontanini G;Santoro M;Gutkind JS
小细胞肺癌（SCLC）通常以Sonic Hedgehog（Shh）通路的上调为特征，导致Gli转录因子的激活。SCLC细胞分泌蛙皮素（BBS）样神经肽（BLP），作为自分泌生长因子。在这里，我们表明，SCLC肿瘤样本的特点是共表达的Shh和BBS同源受体（胃泌素释放肽受体：GRPR）。我们还证明，BBS激活Gli在小细胞肺癌细胞，这是至关重要的BBS介导的小细胞肺癌增殖，因为环巴胺，抑制剂的Shh通路，阻碍了BBS介导的影响。BBS与GRPR结合通过其下游Gαq和Gα12/13 GTP酶刺激Gli，并且一致地，其他Gαq和Gα13偶联受体（如毒蕈碱受体m1和凝血酶受体PAR-1）以及组成型活性GαqQL和Gα12/13 QL突变体刺激Gli。通过使用Gαq和Gα12/13缺失的细胞，我们证明了这些G蛋白对于BBS激活Gli是严格必需的。此外，通过使用组成型活性Rho小G蛋白（Rho QL）及其抑制剂C3毒素，我们表明Rho介导GPCR-，Gαq-和Gα12/13-依赖性Gli刺激。在分子水平上，BBS引起Shh基因转录和蛋白分泌的显著增加，这依赖于BBS诱导的GPCR/Gαq-12/13/Rho介导的NFκB活化，其可刺激Shh基因启动子中的NFκB反应元件。我们的数据确定了一种新的分子网络作用于小细胞肺癌连接自分泌BBS和Shh电路，并建议Shh抑制剂作为新的治疗策略，对这种侵略性的癌症类型。
Small cell lung carcinoma (SCLC) often features the up-regulation of the Sonic Hedgehog (Shh) pathway leading to activation of Gli transcription factors. SCLC cells secrete bombesin (BBS)-like neuropeptides (BLPs) that act as autocrine growth factors. Here, we show that SCLC tumour samples feature co-expression of Shh and BBS-cognate receptor (Gastrin-Releasing Peptide Receptor: GRPR). We also demonstrate that BBS activates Gli in SCLC cells, which is crucial for BBS-mediated SCLC proliferation because cyclopamine, an inhibitor of the Shh pathway, hampered the BBS-mediated effects. BBS binding to GRPR stimulated Gli through its downstream Gαq and Gα12/13 GTPases, and consistently, other Gαq and Gα13 coupled receptors (such as muscarinic receptor, m1, and thrombin receptor, PAR-1) and constitutively active GαqQL and Gα12/13QL mutants stimulated Gli. By using cells null for Gαq and Gα12/13, we demonstrate that these G proteins are strictly necessary for Gli activation by BBS. Moreover, by using constitutively active Rho small G-protein (Rho QL) as well as its inhibitor, C3 toxin, we show that Rho mediates GPCR-, Gαq- and Gα12/13-dependent Gli stimulation. At the molecular level, BBS caused a significant increase in Shh gene transcription and protein secretion that was dependent on BBS-induced GPCR/Gαq-12/13/Rho mediated activation of NFκB, which can stimulate a NFκB response element in the Shh gene promoter. Our data identify a novel molecular network acting in SCLC linking autocrine BBS and Shh circuitries, and suggest Shh inhibitors as novel therapeutic strategies against this aggressive cancer type.