缺氧条件下肺癌细胞中PDE4的形成(Credit: MPI for Heart and Lung Research)
酶可以调节肿瘤细胞的分裂以及癌组织血管的生长，肺癌目前是世界上癌症死亡的一个主要原因，标准的治疗方法通常不会引起长期的疾病恢复，另外，肿瘤细胞的增殖以及血管的生长可以控制肿瘤的形成速度，然而血管的生长又受到很多信号分子的控制，近日，来自德国吉森大学的研究者发现了一种小分子在控制血管生长的过程中扮演者重要作用，实验中，研究者通过封闭磷酸二酯酶PDE4可以成功降低肿瘤的生长速度。相关研究成果刊登在了近日的国际杂志Oncogene上。
肺癌主要影响吸烟者，然而这种癌症可以通过接触致癌物质如石棉来引发，化学疗法和放射线疗法在治疗这种疾病上是无效的，因此，科学家目前正致力于一种新的方法来阻碍肺肿瘤细胞的生长，当然了，血管可以供给肿瘤以营养物质，血管就成为一个潜在的攻击靶点。肿瘤通常会形成新的血管以确保营养的供给，生长的肿瘤组织会很快的渗入新的血管周围。肿瘤细胞可以通过一系列的级联信号来控制并调节血管的生长，这种调节作用会在肿瘤细胞缺氧的时候被触发，这就好像是缺氧促进了肿瘤细胞激活基因表达的能力。另外，缺氧也可以促进肺癌细胞的增殖，三个信号分子在这个过程中扮演着重要的角色，起始阶段，基因的激活是受到转录因子HIF和信使分子cAMP来触发的，研究者检测了第三种信号分子，这种分子连接着前两种信号分子。
第三种信号分子是磷酸二酯酶PDE4，研究者在他们的研究中揭示了PDE4的不同部位结合到HIF结合位点上。研究者随后检测了在10种不同细胞中关闭PDE4所产生的效应，检测结果表明，肿瘤细胞的分裂速度降低了，而且HIF的水平也下降了。在小鼠中进行实验的结果尤为明显，研究者随后再裸鼠皮肤中植入了人类的肿瘤细胞系，并且用磷酸二酯酶抑制剂对其作用，发现肿瘤细胞在裸鼠的体内降低了50%；研究者的显微镜分析揭示了用抑制剂处理的肿瘤细胞，血管生成也明显降低了，而且研究者也观察到了降低肿瘤细胞分裂的指示器。
研究者Werner Seeger报道说，我们揭示了PDE4在调节肿瘤细胞分裂过程中以及肿瘤细胞血管生成上扮演着重要的角色，因此，我们希望我们可以发现一个治疗肺癌的起始点。未来很有可能使用PDE4抑制剂来应用于临床上，如果以这种方式的话，那么传统治疗的效应必须进行强化，而且病人预后会比较好，然而，当前需要更多的临床试验来对这种新疗法进行验证。（生物谷：T.Shen编译）
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doi:10.1038/onc.2012.136
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Phosphodiesterase-4 promotes proliferation and angiogenesis of lung cancer by crosstalk with HIF
S S Pullamsetti, G A Banat, A Schmall, M Szibor, D Pomagruk, J Hänze, E Kolosionek, J Wilhelm, T Braun, F Grimminger, W Seeger, R T Schermuly and R Savai
Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that cyclic nucleotide phosphodiesterases (PDEs) are relevant in various cancer pathologies. Pathophysiological role of phosphodiesterase 4 (PDE4) with possible therapeutic prospects in lung cancer was investigated. We exposed 10 different lung cancer cell lines (adenocarcinoma, squamous and large cell carcinoma) to hypoxia and assessed expression and activity of PDE4 by real-time PCR, immunocytochemistry, western blotting and PDE activity assays. Expression and activity of distinct PDE4 isoforms (PDE4A and PDE4D) increased in response to hypoxia in eight of the studied cell lines. Furthermore, we analyzed various in silico predicted hypoxia-responsive elements (p-HREs) found in in PDE4A and PDE4D genes. Performing mutation analysis of the p-HRE in luciferase reporter constructs, we identified four functional HRE sites in the PDE4A gene and two functional HRE sites in the PDE4D gene that mediated hypoxic induction of the reporter. Silencing of hypoxia-inducible factor subunits (HIF1α and HIF2α) by small interfering RNA reduced hypoxic induction of PDE4A and PDE4D. Vice versa, using a PDE4 inhibitor (PDE4i) as a cyclic adenosine monophosphate (cAMP) -elevating agent, cAMP analogs or protein kinase A (PKA)-modulating drugs and an exchange protein directly activated by cAMP (EPAC) activator, we demonstrated that PDE4-cAMP-PKA/EPAC axis enhanced HIF signaling as measured by HRE reporter gene assay, HIF and HIF target genes expression ((lactate dehydrogenase A), LDHA, (pyruvate dehydrogenase kinase 1) PDK1 and (vascular endothelial growth factor A) VEGFA). Notably, inhibition of PDE4 by PDE4i or silencing of PDE4A and PDE4D reduced human lung tumor cell proliferation and colony formation. On the other hand, overexpression of PDE4A or PDE4D increased human lung cancer proliferation. Moreover, PDE4i treatment reduced hypoxia-induced VEGF secretion in human cells. In vivo, PDE4i inhibited tumor xenograft growth in nude mice by attenuating proliferation and angiogenesis. Our findings suggest that PDE4 is expressed in lung cancer, crosstalks with HIF signaling and promotes lung cancer progression. Thus, PDE4 may represent a therapeutic target for lung cancer therapy.
