Growth suppression of lung cancer cells by targeting cyclic AMP response element-binding protein
Growth suppression of lung cancer cells by targeting cyclic AMP response element-binding protein
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DOI：
10.1158/0008-5472.can-06-0249
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发表时间：
2008-02-15
期刊：
影响因子：
11.2
通讯作者：
Koo, Ja Seok
中科院分区：
文献类型：
--
作者：
Aggarwal, Sita;Kim, Seung-Wook;Koo, Ja Seok
据报道，环amp反应元件结合蛋白（CREB）调控的基因可抑制细胞凋亡，诱导细胞增殖，介导炎症和肿瘤转移。然而，目前尚不清楚CREB是否在肺癌发生中起关键作用。我们发现，非小细胞肺癌（NSCLC）细胞系在CREB、其直接上游激酶（核糖体s6激酶和细胞外信号激酶）以及CREB调节的细胞存活蛋白Bcl-2和Bcl-xL中表现出升高的组成活性。我们假设组成活性CREB对肺癌细胞的生长和存活很重要，因此可能是非小细胞肺癌的潜在治疗靶点。异位表达显性抑制因子CREB和转染小干扰RNA抑制CREB可抑制非小细胞肺癌细胞的生长和存活，并诱导凋亡细胞死亡。此外，用CREB信号通路抑制剂Ro-31-8220处理H1734 NSCLC细胞，通过阻断细胞外信号激酶和核糖体s6激酶的活性，抑制CREB的激活，使细胞周期停留在G(2)-M期，随后通过抑制Bcl-2和Bcl-xL的表达诱导细胞凋亡。Ro-31-8220抑制非小细胞肺癌细胞的锚定依赖性和独立生长，但其对正常支气管上皮细胞的细胞毒性作用不明显。我们的研究结果表明，活跃的CREB在非小细胞肺癌细胞的生长和存活中起着重要作用。因此，抑制CREB激活的药物可能对非小细胞肺癌治疗具有潜在的治疗价值。
Genes regulated by cyclic AMP-response element-binding protein (CREB) have been reported to suppress apoptosis, induce cell proliferation, and mediate inflammation and tumor metastasis. However, it is not clear whether CREB is critically involved in lung carcinogenesis. We found that non-small cell lung cancer (NSCLC) cell lines exhibited elevated constitutive activity in CREB, in its immediate upstream kinases (ribosomal s6 kinase and extracellular signal kinase), and in the CREB-regulated cell survival proteins Bcl-2 and Bcl-xL. We hypothesized that constitutively active CREB is important to lung cancer cell growth and survival and therefore could be a potential therapeutic target for NSCLC. Ectopic expression of dominant repressor CREB and transfection with small interfering RNA against CREB suppressed the growth and survival of NSCLC cells and induced apoptotic cell death. Furthermore, treating H1734 NSCLC cells with an inhibitor of the CREB signaling pathway Ro-31-8220 inhibited CREB activation by blocking the activity of extracellular signal kinase and ribosomal s6 kinase, arrested the cell cycle at the G(2)-M phase, and subsequently induced apoptosis with the suppression of Bcl-2 and Bcl-xL expression. Ro-31-8220 suppressed both the anchorage-dependent and independent growth of NSCLC cells, but its cytotoxic effect was much less prominent in normal bronchial epithelial cells. Our results indicate that active CREB plays an important role in NSCLC cell growth and survival. Thus, agents that suppress CREB activation could have potential therapeutic value for NSCLC treatment.