Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma.
Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma.
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DOI：
10.1093/carcin/bgn041
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发表时间：
2008-10
期刊：
影响因子：
4.7
通讯作者：
Majidi, Mourad
中科院分区：
文献类型：
--
作者：
Schuller, Hildegard M.;Al-Wadei, Hussein A. N.;Majidi, Mourad
肺腺癌（PAC）是吸烟者和非吸烟者的主要肺癌类型，在大多数情况下由小气道上皮细胞引起。由于其侵袭性行为和对癌症治疗的耐药性，PAC具有很高的死亡率。我们之前已经证明，人PAC细胞NCI-H322和永生化人小气道上皮细胞HPL1D的增殖受到环磷酸腺苷(cAMP)/蛋白激酶a依赖的环磷酸腺苷反应元件结合（CREB）蛋白磷酸化和表皮生长因子受体的反激活的刺激，并且该途径由β -1-肾上腺素受体（β1-ARs）和非基因组雌激素受体β激活。我们目前对HPL1D和NCI-H322细胞的体外研究表明，通过γ -氨基丁酸受体（GABABR）的信号传导强烈抑制碱基水平和异丙肾上腺素诱导的cAMP、p-CREB、环腺苷单磷酸反应元件-荧光素酶活性和p-细胞外调节激酶-1 (ERK1)/2，并有效阻断DNA合成和细胞迁移。γ -氨基丁酸（GABA）的抑制作用可通过GABABR拮抗剂CGP-35348或GABABR敲低来解除。对仓鼠肺的免疫组化研究显示，在尼古丁衍生致癌物4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）诱导的小气道源性PACs中，GABA的表达明显不足。这些发现表明，GABA可能在小气道上皮及其衍生的pac中具有肿瘤抑制功能，并且NNK下调GABA可能有助于吸烟者发生这种癌症。我们的研究结果表明，用GABA或GABABR激动剂对肺GABA下调的个体进行标记引导治疗可能为吸烟者预防PAC提供一种新的靶向方法。
Pulmonary adenocarcinoma (PAC) is the leading type of lung cancer in smokers and non-smokers that arises in most cases from small airway epithelial cells. PAC has a high mortality due to its aggressive behavior and resistance to cancer therapeutics. We have shown previously that the proliferation of human PAC cells NCI-H322 and immortalized human small airway epithelial cells HPL1D is stimulated by cyclic adenosine monophosphate (cAMP)/protein kinase A-dependent phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein and transactivation of the epidermal growth factor receptor and that this pathway is activated by beta-1-adrenoreceptors (β1-ARs) and the non-genomic estrogen receptor beta. Our current in vitro studies with HPL1D and NCI-H322 cells showed that signaling via the gamma-amino butyric acid receptor (GABABR) strongly inhibited base level and isoproterenol-induced cAMP, p-CREB, cyclic adenosine monophosphate response element-luciferase activity and p-extracellular regulated kinase-1 (ERK1)/2 and effectively blocked DNA synthesis and cell migration. The inhibitory effects of gamma-amino butyric acid (GABA) were disinhibited by the GABABR antagonist CGP-35348 or GABABR knockdown. Immunohistochemical investigation of hamster lungs showed significant underexpression of GABA in animals with small airway-derived PACs induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These findings suggest that GABA may have tumor suppressor function in small airway epithelia and the PACs derived from them and that downregulation of GABA by NNK may contribute to the development of this cancer in smokers. Our findings suggest that marker-guided treatment with GABA or a GABABR agonist of individuals with downregulated pulmonary GABA may provide a novel targeted approach for the prevention of PAC in smokers.
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影响因子：
11.2
作者：
Majidi, Mourad;Al-Wadei, Hussein A.;Schuller, Hildegard M.
通讯作者：
Schuller, Hildegard M.
影响因子：
9.6
作者：
Albertine, KH;Steiner, RM;Farber, JL
通讯作者：
Farber, JL
影响因子：
10.6
作者：
Epperson, CN;O'Malley, S;Mason, GF
通讯作者：
Mason, GF
影响因子：
3.6
作者：
Schuller, HM;Porter, B;Riechert, A
通讯作者：
Riechert, A
影响因子：
6.4
作者：
Lang, K;Drell, TL;Entschladen, F
通讯作者：
Entschladen, F