Role of soluble guanylyl cyclase-cyclic GMP signaling in tumor cell proliferation.-猫眼课题宝

DOI：

10.1016/j.niox.2009.11.007

发表时间：

2010-01-01

期刊：

Nitric oxide : biology and chemistry

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Mujoo K;Sharin VG;Martin E;Choi BK;Sloan C;Nikonoff LE;Kots AY;Murad F

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838505/?report=classic

我们之前的研究表明，胚胎干细胞中一氧化氮（NO）信号成分的差异表达，我们最近的研究表明，在一氧化氮供体和可溶性冠酰环化酶（sGC）激活剂的作用下，胚胎干细胞向心肌细胞的分化增强。由于NO- cgmp通路在癌症中表现出多种作用，我们有兴趣评估NO受体sGC和该通路的其他成分在调节肿瘤细胞增殖中的作用。我们的研究结果表明，在不同的人类癌症模型中，sGC亚基、NOS-1和PKG mRNA和蛋白水平的表达存在差异。与sGCα1相比，sGC β1在OVCAR-3（卵巢癌）和MDA-MB-468（乳腺癌）细胞中表达水平较高，在NO供体和sGC激活剂联合作用下，sGC β1与sGC活性密切相关，cGMP水平显著升高。NOC-18 （DETA NONOate； NO供体），BAY41-2272（3-（4-氨基-5-环丙基嘧啶-2-基）-1-（2-氟苯基）- 1h -吡唑[3,4-b]吡啶）；sGC激活剂)、NOC-18+BAY41-2272、IBMX（3-异丁基-1-甲基黄嘌呤；磷酸二酯酶抑制剂）和8-溴-cGMP （cGMP类似物）可抑制多种癌细胞的生长和凋亡。为了阐明生长抑制的分子机制，我们评估了激活剂/抑制剂对ERK磷酸化的影响。我们的研究表明，BAY41-2272或no18 +BAY41-2272在OVCAR-3（高sGC活性）、SK-OV-3和SK-Br-3（低sGC活性）细胞系中引起ERK1/2基础磷酸化的抑制，在某些情况下，这种抑制被sGC抑制剂ODQ （1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one）所恢复。这些研究表明NO-sGC-cGMP激活剂/抑制剂对肿瘤细胞增殖的影响是由cgmp依赖和独立的机制介导的。

Our previous studies demonstrate a differential expression of nitric oxide (NO) signaling components in ES cells and our recent study demonstrated an enhanced differentiation of ES cells into myocardial cells with NO donors and soluble guanylyl cyclase (sGC) activators. Since NO-cGMP pathway exhibits a diverse role in cancer, we were interested in evaluating the role of the NO receptor sGC and other components of the pathway in regulation of the tumor cell proliferation. Our results demonstrate a differential expression of the sGC subunits, NOS-1 and PKG mRNA and protein levels in various human cancer models. In contrast to sGCα1, robust levels of sGC β1 were observed in OVCAR-3 (ovarian) and MDA-MB-468 (breast) cancer cells which correlated well with the sGC activity and a marked increase in cGMP levels upon exposure to the combination of a NO donor and a sGC activator. NOC-18 (DETA NONOate; NO donor), BAY41-2272 (3-(4-Amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine); sGC activator), NOC-18+BAY41-2272, IBMX (3-Isobutyl-1-methylxanthine; phosphodiesterase inhibitor) and 8-bromo-cGMP (cGMP analog) caused growth inhibition and apoptosis in various cancer cell lines. To elucidate the molecular mechanisms involved in growth inhibition, we evaluated the effect of activators/inhibitors on ERK phosphorylation. Our studies indicate that BAY41-2272 or the combination NOC18+BAY41-2272 caused inhibition of the basal ERK1/2 phosphorylation in OVCAR-3 (high sGC activity), SK-OV-3 and SK-Br-3 (low sGC activity) cell lines and in some cases the inhibition was rescued by the sGC inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). These studies suggest that the effects of activators/inhibitors of NO-sGC-cGMP in tumor cell proliferation is mediated by both cGMP-dependent and independent mechanisms.