Departments of Hematology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Mol Pharmacol. 2011 Dec;80(6):1076-84. doi: 10.1124/mol.111.073585. Epub 2011 Sep 9.
The NO and cGMP signaling pathways are of broad physiological and pathological significance. We compared the NO/soluble guanylyl cyclase (sGC)/cGMP pathway in human glioma tissues and cell lines with that of healthy control samples and demonstrated that sGC expression is significantly lower in glioma preparations. Our analysis of GEO databases (National Cancer Institute) further revealed a statistically significant reduction of sGC transcript levels in human glioma specimens. On the other hand, the expression levels of particulate (membrane) guanylyl cyclases (pGC) and cGMP-specific phosphodiesterase (PDE) were intact in the glioma cells that we have tested. Pharmacologically manipulating endogenous cGMP generation in glioma cells through either stimulating pGC by ANP/BNP, or blocking PDE by 3-isobutyl-1-methylxanthine/zaprinast caused significant inhibition of proliferation and colony formation of glioma cells. Genetically restoring sGC expression also correlated inversely with glioma cells growth. Orthotopic implantation of glioma cells transfected with an active mutant form of sGC (sGCα1β1(Cys105)) in athymic mice increased the survival time by 4-fold over the control. Histological analysis of xenografts overexpressing α1β1(Cys105) sGC revealed changes in cellular architecture that resemble the morphology of normal cells. In addition, a decrease in angiogenesis contributed to glioma inhibition by sGC/cGMP therapy. Our study proposes the new concept that suppressed expression of sGC, a key enzyme in the NO/cGMP pathway, may be associated with an aggressive course of glioma. The sGC/cGMP signaling-targeted therapy may be a favorable alternative to chemotherapy and radiotherapy for glioma and perhaps other tumors.
NO 和 cGMP 信号通路具有广泛的生理和病理意义。我们比较了人胶质瘤组织和细胞系中的 NO/可溶性鸟苷酸环化酶 (sGC)/cGMP 通路与健康对照样本中的通路，结果表明 sGC 表达在胶质瘤制剂中显著降低。我们对 GEO 数据库（美国国立癌症研究所）的分析进一步显示，人胶质瘤标本中 sGC 转录本水平存在统计学上的显著降低。另一方面，我们测试的胶质瘤细胞中颗粒（膜）鸟苷酸环化酶 (pGC) 和 cGMP 特异性磷酸二酯酶 (PDE) 的表达水平完整。通过刺激 pGC 使内源性 cGMP 生成在胶质瘤细胞中受到药理学操纵，通过 ANP/BNP 或通过 3-异丁基-1-甲基黄嘌呤/扎普司特阻断 PDE，导致胶质瘤细胞增殖和集落形成受到显著抑制。通过基因恢复 sGC 表达也与胶质瘤细胞生长呈负相关。将转染了 sGC 活性突变体（sGCα1β1(Cys105)）的胶质瘤细胞原位植入无胸腺小鼠中，使对照小鼠的存活时间增加了 4 倍。过表达α1β1(Cys105)sGC 的异种移植物的组织学分析显示，细胞结构发生了变化，类似于正常细胞的形态。此外，sGC/cGMP 治疗可减少血管生成，从而抑制胶质瘤。我们的研究提出了一个新概念，即 NO/cGMP 通路的关键酶 sGC 表达受抑制可能与胶质瘤的侵袭性病程有关。sGC/cGMP 信号靶向治疗可能是化疗和放疗的有利替代方案，适用于胶质瘤和其他肿瘤。
