Muscarinic regulation of SCA-9 cell proliferation via nitric oxide synthases, 6 arginases and cyclooxygenases. Role of the nuclear translocation factor-κB

ALEJANDRO ESPAÑOL; DASSO MAXIMILIANO; CELLA MAXIMILIANO; GOREN NORA; SALES MARIA ELENA

EUROPEAN JOURNAL OF PHARMACOLOGY

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2012 vol. 683 p. 43 - 53

0014-2999

The submandibular gland-derived tumor cell line SCA-9 is considered a useful tool to study the signaling 24 pathways involved in proliferation, and their regulation, triggered by different stimuli. It is proposed that 25 the non neuronal cholinergic system: acethylcholine, the enzymes that synthesize and degrade it, and the 26 nicotinic and muscarinic receptors, play a key role in tumorigenesis. Here, we investigate the role of musca- 27 rinic receptors in SCA-9 cell proliferation, and the modulation of cholinergic signaling pathways exerted by 28 the nuclear transcription factor κB (NF-κB). The activation of cholinergic receptors by carbachol (10−9 M) in- 29 creased cell proliferation (Pb0.001). This was prevented by preincubating cells with the muscarinic antago- 30 nist atropine but not by mecamylamine, a nicotinic receptor blocker. Phospholipase C (PLC)/nitric oxide 31 synthase (NOS)/arginase pathway is involved in this effect, since carbachol stimulated nitric oxide produc- 32 tion, increased NOS2 and NOS3 expressions, urea production, and arginase II expression (Pb0.001). Also, 33 phospholipase A2 (PLA2)/cyclooxygenase (COX) pathway is up-regulated in carbachol-induced SCA-9 cell 34 proliferation, because prostaglandin E2 liberation (Pb0.001) is increased and COX-1 expression is turned 35 up (Pb0.001). Interactions between PLC/NOS/arginases and PLA2/COX pathways via its metabolites were 36 detected. SCA-9 cells exhibit a constitutive activation of NF-κB, which regulates carbachol-induced NOS2 37 and 3, arginase II and COX-1 expressions. In addition, protein kinase C is involved in the up-regulation of 38 NOS2 and arginase II enzymes induced by carbachol via NF-κB. In conclusion, the activation of cholinergic re- 39 ceptors in SCA-9 tumor cells promotes proliferation via muscarinic effector enzymes, and reveals the partic- 40 ipation of NF-κB at this step of tumorigenesis.