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The prostanoid biosynthetic enzyme cyclooxygenase-2 (Cox-2) is up-regulated in several neuroendocrine tumors. The aim of the current study was to employ a neuroendocrine cell (PC12) model of Cox-2 overexpression to identify gene products that might be implicated in the oncogenic and/or inflammatory actions of this enzyme in the setting of neuroendocrine neoplasia. Expression array and real-time PCR analysis demonstrated that levels of the neuroendocrine marker chromogranin A (CGA) were 2- and 3.2-fold higher, respectively, in Cox-2 overexpressing cells (PCXII) vs. their control (PCMT) counterparts. Immunocytochemical and immunoblotting analyses confirmed that both intracellular and secreted levels of CGA were elevated in response to Cox-2 induction. Moreover, exogenous addition of prostaglandin E(2) (1 microm) mimicked this effect in PCMT cells, whereas treatment of PCXII cells with the Cox-2 selective inhibitor NS-398 (100 nm) reduced CGA expression levels, thereby confirming the biospecificity of this finding. Levels of neuron-specific enolase were similar in the two cell lines, suggesting that the effect of Cox-2 on CGA expression was specific and not due to a global enhancement of neuroendocrine marker expression/differentiation. Cox-2-dependent CGA up-regulation was associated with significantly increased chromaffin granule number and intracellular and secreted levels of dopamine. CGA promoter-driven reporter gene expression studies provided evidence that prostaglandin E(2)-dependent up-regulation required a proximal cAMP-responsive element (-71 to -64 bp). This study is the first to demonstrate that Cox-2 up-regulates both CGA expression and bioactivity in a neuroendocrine cell line and has major implications for the role of this polypeptide in the pathogenesis of neuroendocrine cancers in which Cox-2 is up-regulated.

endocrinology

Cox-2 Promotes Chromogranin A Expression and Bioactivity: Evidence for a Prostaglandin E2-Dependent Mechanism and the Involvement of a Proximal Cyclic Adenosine 5′-Monophosphate-Responsive Element