Muscarinic regulation of SCA-9 cell proliferation via nitric oxide synthases, arginases and cyclooxygenases. Role of the nuclear translocation factor-魏B

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• 作者：Alejandro Españ ; ol^a ; Maximiliano Dasso^a ; Maximiliano Cella^a ; Nora Goren^b ; Marí ; a Elena Sales^a ; ^{malegazpio@yahoo.com.ar}
• 关键词：Muscarinic receptor ; Nitric oxide synthase ; Arginase ; Cyclooxygenase ; Protein kinase C ; Nuclear transcription factor 魏B
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：15 May, 2012
• 卷：683
• 期：1-3
• 页码：43-53
• 文件大小：1012 K

摘要

The submandibular gland-derived tumor cell line SCA-9 is considered a useful tool to study the signaling pathways involved in proliferation, and their regulation, triggered by different stimuli. It is proposed that the non neuronal cholinergic system: acethylcholine, the enzymes that synthesize and degrade it, and the nicotinic and muscarinic receptors, play a key role in tumorigenesis. Here, we investigate the role of muscarinic receptors in SCA-9 cell proliferation, and the modulation of cholinergic signaling pathways exerted by the nuclear transcription factor 魏B (NF-魏B). The activation of cholinergic receptors by carbachol (10^鈭?#xA0;9 M) increased cell proliferation (P < 0.001). This was prevented by preincubating cells with the muscarinic antagonist atropine but not by mecamylamine, a nicotinic receptor blocker. Phospholipase C (PLC)/nitric oxide synthase (NOS)/arginase pathway is involved in this effect, since carbachol stimulated nitric oxide production, increased NOS2 and NOS3 expressions, urea production, and arginase II expression (P < 0.001). Also, phospholipase A₂ (PLA₂)/cyclooxygenase (COX) pathway is up-regulated in carbachol-induced SCA-9 cell proliferation, because prostaglandin E₂ liberation (P < 0.001) is increased and COX-1 expression is turned up (P < 0.001). Interactions between PLC/NOS/arginases and PLA₂/COX pathways via its metabolites were detected. SCA-9 cells exhibit a constitutive activation of NF-魏B, which regulates carbachol-induced NOS2 and 3, arginase II and COX-1 expressions. In addition, protein kinase C is involved in the up-regulation of NOS2 and arginase II enzymes induced by carbachol via NF-魏B. In conclusion, the activation of cholinergic receptors in SCA-9 tumor cells promotes proliferation via muscarinic effector enzymes, and reveals the participation of NF-魏B at this step of tumorigenesis.