The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma.
The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma.
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DOI：
10.1016/j.canlet.2015.10.024
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发表时间：
2016-01-28
期刊：
影响因子：
9.7
通讯作者：
Ben-Jonathan N
中科院分区：
文献类型：
--
作者：
Tuttle TR;Mierzwa ML;Wells SI;Fox SR;Ben-Jonathan N
头颈部鳞状细胞癌(HNSCC)是一种高死亡率的侵袭性疾病。治疗方法可能会导致严重的发病率，但三十年来没有实质性的变化。针对蛋白激酶G(PKG)的第二信使环GMP(CGMP)由鸟苷环化酶(GCs)产生，并被磷酸二酯酶(PDE)迅速降解。在一些癌症类型中，cGMP/PKG通路的激活是抗肿瘤的，但其在HNSCC中的作用尚未被充分利用。我们发现该途径的关键成分在四个HNSCC细胞系中的表达存在差异。几种可溶性GC激活剂和PDE5抑制剂可增加细胞内cGMP，降低细胞存活率，诱导HNSCC细胞凋亡。SGC激活剂Bay 41-2272和PDE5抑制剂他达拉非(Cialis)通过PKG介导细胞凋亡。此外，他达拉非显著减少了无瘤小鼠CAL27来源的肿瘤的生长。几种激活sGC或抑制PDE5的药物已被批准用于治疗非恶性疾病。这些药物可能会被重新用于头颈癌患者的新的有效治疗。
Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease with high mortality. Treatments, which can result in significant morbidity, have not substantially changed in three decades. The second messenger cyclic GMP (cGMP), which targets protein kinase G (PKG), is generated by guanylate cyclases (GCs), and is rapidly hydrolyzed by phosphodiesterases (PDEs). Activation of the cGMP/PKG pathway is antineoplastic in several cancer types, but its impact on HNSCC has not been fully exploited. We found differential expression of critical components of this pathway in four HNSCC cell lines. Several activators of soluble GC (sGC), as well as inhibitors of PDE5, increased intracellular cGMP, reduced cell viability, and induced apoptosis in HNSCC cells. The apoptotic effects of the sGC activator BAY 41-2272 and the PDE5 inhibitor Tadalafil (Cialis) were mediated by PKG. Furthermore, Tadalafil substantially reduced the growth of CAL27-derived tumors in athymic mice. Several drugs which either activate sGC or inhibit PDE5 are approved for treatment of nonmalignant conditions. These drugs could be repurposed as novel and effective therapeutics in patients with head and neck cancer.