EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways
EP2 prostanoid receptor promotes squamous cell carcinoma growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways
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DOI：
10.1096/fj.06-7581com
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发表时间：
2007-08-01
期刊：
影响因子：
4.8
通讯作者：
Ziche, Marina
中科院分区：
文献类型：
--
作者：
Donnini, Sandra;Finetti, Federica;Ziche, Marina
在鳞状细胞癌中，来自肿瘤细胞或肿瘤相关炎性细胞的诱导型NO合酶（iNOS）的一氧化氮（NO）和来自环氧合酶-2（考克斯-2）的前列腺素E-2（PGE（2））的水平已被报道与肿瘤生长、转移和血管生成相关。本研究检测了iNOS信号通路在PGE（2）介导的鳞状细胞癌、A431和SCC-9细胞的肿瘤侵袭和增殖中的作用。iNOS沉默RNA或iNOS/鸟苷酸环化酶（GC）药理学抑制可阻断PGE 2促进的细胞侵袭和增殖。同样，iNOS-GC通路抑制剂阻断了丝裂原活化蛋白激酶-ERK 1/2磷酸化，这是介导PGE 2功能所必需的。在体内，在裸鼠移植的A431细胞中，GC抑制也降低了肿瘤增殖指数和ERK 1/2活化。PGE 2的作用仅限于选择性刺激EP 2受体亚型，通过蛋白激酶A（PKA）和c-Src激活导致表皮生长因子受体（EGFR）的反式激活。EP 2介导的ERK 1/2激活和细胞功能被PKA、c-Src和EGFR的抑制剂以及通过抑制iNOS途径消除。iNOS的沉默也损害EGFR诱导的ERK 1/2磷酸化。这些结果表明，iNOS/GC信号转导是控制EP 2/EGFR介导的肿瘤细胞增殖和侵袭的下游参与者。
In squamous cell carcinoma, the levels of nitric oxide ( NO) derived from inducible NO synthase ( iNOS) and prostaglandin E-2 ( PGE(2)) derived from cyclooxygenase-2 ( COX-2) originated from tumor cells or tumor-associated inflammatory cells have been reported to correlate with tumor growth, metastasis, and angiogenesis. The present study examined the role of the iNOS signaling pathway in PGE(2)-mediated tumor invasiveness and proliferation in squamous cell carcinoma, A431, and SCC-9 cells. Cell invasion and proliferation promoted by PGE2 were blocked by iNOS silencing RNA or iNOS/guanylate cyclase ( GC) pharmacological inhibition. Consistently, iNOS-GC pathway inhibitors blocked mitogen-activated protein kinase-ERK1/2 phosphorylation, which was required to mediate PGE2 functions. In vivo, in A431 cells implanted in nude mice, GC inhibition also decreased the tumor proliferation index and ERK1/2 activation. PGE2 effects were confined to the selective stimulation of the EP2 receptor subtype, leading to epidermal growth factor receptor ( EGFR) transactivation via protein kinase A ( PKA) and c-Src activation. EP2-mediated ERK1/2 activation and cell functions were abolished by inhibitors of PKA, c-Src, and EGFR, as well as by inhibiting iNOS pathway. Silencing of iNOS also impaired EGFR-induced ERK1/2 phosphorylation. These results indicate that iNOS/GC signaling is a downstream player in the control of EP2/EGFR-mediated tumor cell proliferation and invasion.