缺氧條件下肺癌細(xì)胞中PDE4的形成(Credit: MPI for Heart and Lung Research)
酶可以調(diào)節(jié)腫瘤細(xì)胞的分裂以及癌組織血管的生長,，肺癌目前是世界上癌癥死亡的一個(gè)主要原因,，標(biāo)準(zhǔn)的治療方法通常不會(huì)引起長期的疾病恢復(fù),，另外，腫瘤細(xì)胞的增殖以及血管的生長可以控制腫瘤的形成速度，然而血管的生長又受到很多信號(hào)分子的控制，近日，來自德國吉森大學(xué)的研究者發(fā)現(xiàn)了一種小分子在控制血管生長的過程中扮演者重要作用,，實(shí)驗(yàn)中，研究者通過封閉磷酸二酯酶PDE4可以成功降低腫瘤的生長速度。相關(guān)研究成果刊登在了近日的國際雜志Oncogene上,。
肺癌主要影響吸煙者,，然而這種癌癥可以通過接觸致癌物質(zhì)如石棉來引發(fā)，化學(xué)療法和放射線療法在治療這種疾病上是無效的,，因此,，科學(xué)家目前正致力于一種新的方法來阻礙肺腫瘤細(xì)胞的生長，當(dāng)然了,，血管可以供給腫瘤以營養(yǎng)物質(zhì),，血管就成為一個(gè)潛在的攻擊靶點(diǎn)。腫瘤通常會(huì)形成新的血管以確保營養(yǎng)的供給,，生長的腫瘤組織會(huì)很快的滲入新的血管周圍,。腫瘤細(xì)胞可以通過一系列的級(jí)聯(lián)信號(hào)來控制并調(diào)節(jié)血管的生長，這種調(diào)節(jié)作用會(huì)在腫瘤細(xì)胞缺氧的時(shí)候被觸發(fā),，這就好像是缺氧促進(jìn)了腫瘤細(xì)胞激活基因表達(dá)的能力,。另外，缺氧也可以促進(jìn)肺癌細(xì)胞的增殖,，三個(gè)信號(hào)分子在這個(gè)過程中扮演著重要的角色,，起始階段，基因的激活是受到轉(zhuǎn)錄因子HIF和信使分子cAMP來觸發(fā)的,，研究者檢測了第三種信號(hào)分子,，這種分子連接著前兩種信號(hào)分子。
第三種信號(hào)分子是磷酸二酯酶PDE4,，研究者在他們的研究中揭示了PDE4的不同部位結(jié)合到HIF結(jié)合位點(diǎn)上,。研究者隨后檢測了在10種不同細(xì)胞中關(guān)閉PDE4所產(chǎn)生的效應(yīng)，檢測結(jié)果表明,，腫瘤細(xì)胞的分裂速度降低了,，而且HIF的水平也下降了。在小鼠中進(jìn)行實(shí)驗(yàn)的結(jié)果尤為明顯,，研究者隨后再裸鼠皮膚中植入了人類的腫瘤細(xì)胞系,，并且用磷酸二酯酶抑制劑對其作用，發(fā)現(xiàn)腫瘤細(xì)胞在裸鼠的體內(nèi)降低了50%,；研究者的顯微鏡分析揭示了用抑制劑處理的腫瘤細(xì)胞,，血管生成也明顯降低了，而且研究者也觀察到了降低腫瘤細(xì)胞分裂的指示器,。
研究者Werner Seeger報(bào)道說,，我們揭示了PDE4在調(diào)節(jié)腫瘤細(xì)胞分裂過程中以及腫瘤細(xì)胞血管生成上扮演著重要的角色,，因此,，我們希望我們可以發(fā)現(xiàn)一個(gè)治療肺癌的起始點(diǎn)。未來很有可能使用PDE4抑制劑來應(yīng)用于臨床上，如果以這種方式的話,，那么傳統(tǒng)治療的效應(yīng)必須進(jìn)行強(qiáng)化,，而且病人預(yù)后會(huì)比較好，然而,，當(dāng)前需要更多的臨床試驗(yàn)來對這種新療法進(jìn)行驗(yàn)證,。（生物谷：T.Shen編譯）
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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.
