Indometacin Ameliorates High Glucose-Induced Proliferation and Invasion Via Modulation of E-Cadherin in Pancreatic Cancer Cells

Abstract

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.

High Glucose Promotes Tumor Invasion and Increases Metastasis-Associated Protein Expression in Human Lung Epithelial Cells by Upregulating Heme Oxygenase-1 via Reactive Oxygen Species or the TGF-β1/PI3K/Akt Signaling Pathway

“…In the present study, our findings demonstrated that HG increased HO-1 protein expression via ROS or the TGF-β 1 /PI3K/Akt signaling pathway, which mediated tumor cell invasion and metastasis-associated protein expression, and indicated that HO-1 may serve as a potential therapeutic target in lung cancer. This result is also supported by previous reports [11,12,35,44,45]. This conclusion was supported by four primary findings in the present study.…”

“…Several lines of evidence have indicated that HG enhances the invasiveness potential of MCF-7 breast cancer cells [44,59] and of pancreatic cancer cells [45,60]. Furthermore, previous studies have indicated that HO-1 positively correlates with tumor stage and lymph node metastasis and that HO-1 is associated with NSCLC progression [31].…”

Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma

“…This promotes cell proliferation, 33 increases the expression of Snail and Slug inducing EMT transition, 34, 35 and elevates secretion of MMP2 and MMP9 facilitating cell invasion. 36 Our results suggest that inactivated PI3K/AKT signaling is responsible for shRNA-FAP-mediated suppression of tumor cell proliferation, adhesion, invasion, and EMT. In addition, it has a role in hypophosphorylation of GSK3b, attenuated expression of c-Myc, pRB, CCNE1, E2F1, Snail, Slug, Vimentin, N-cadherin, MMP2, MMP9, and elevated expression of p21, p27, and E-cadherin in OSCC cells.…”

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling

“…Furthermore, the acidification may also lead to increased activation of matrix metalloproteinases (MMPs) activities [24]. High glucose has been previously shown to increase lactate production and decrease E-cadherin protein expression in colon, breast, bladder and pancreatic cancer cells [24, 26]. Cancer cells with low E-cadherin expression are more prone to evade a tumor mass and to invade the surrounding tissue.…”