Indometacin, an inhibitor of cyclooxygenase-2 (COX-2), has been shown to exert anticancer effects in a variety
of cancers. However, the effect and mechanism of indometacin on high glucose (HG)-induced proliferation and invasion
of pancreatic cancer (PC) cells remain unclear. Multiple lines of evidence suggest that a large portion of pancreatic cancer
(PC) patients suffer from either diabetes or HG which contributing PC progression. In this study, we report that indometacin
down-regulated HG-induced proliferation and invasion via up-regulating E-cadherin but not COX-2 in PC cells.
Additionally, the E-cadherin transcriptional repressors, Snail and Slug, were also involved in the process. Furthermore, the
proliferation and invasion of PC cells, incubated in HG medium and treated with indometacin were significantly increased
when E-cadherin was knocked down (Si-E-cad). Moreover, the protein levels of MMP-2, MMP-9, and VEGF were increased
in PC cells transfected with Si-E-cad. Finally, the activation of the PI3K/AKT/GSK-3β signaling pathway was
demonstrated to be involved in indometacin reversing HG-induced cell proliferation and invasion in PC cells. In conclusion,
these results suggest that indometacin plays a key role in down-regulating HG-induced proliferation and invasion in
PC cells. Our findings indicate that indometacin could be used as a novel therapeutic strategy to treat PC patients who simultaneously
suffer from diabetes or HG.
Keywords: Cancer progression, COX-2, E-cadherin, high glucose, indometacin, invasion, pancreatic cancer, PI3K/AKT, proliferation,
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