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Glycogen synthase kinase-3? activity plays a key role in the antitumor effect of nafamostat mesilate in pancreatic cancer cells.

ABSTRACT: Pancreatic cancer is often resistant to chemotherapy. We previously showed the efficacy of combination treatment using gemcitabine and nafamostat mesilate (FUT-175) for patients with unresectable pancreatic cancer. However, the mechanisms that affect the sensitivity of FUT-175 are not fully understood. The purpose of the present study was to clarify the mechanism of the sensitivity to FUT-175, with a focus on the activity of glycogen synthase kinase-3? (GSK-3?). In vitro, we assessed sensitivity to FUT-175 in human pancreatic cancer cell lines (PANC-1 and MIAPaCa-2) and difference of signaling in these cells by cell proliferation assay, Western blot analysis and microarray. Next, we assessed cell viability, apoptotic signal and nuclear factor-kappa B (NF-?B) activity in response to treatment with FUT-175 alone and in combination with GSK-3 inhibitor or protein phosphatase 2A (PP2A) by cell proliferation assay, Western blot analysis and enzyme-linked immunosorbent assay. Phosphorylated GSK-3? level was significantly higher in MIAPaCa-2 (high sensitivity cell) than in PANC-1 (low sensitivity cell). Cell viability and NF-?B activity were significantly decreased by addition of GSK-3 inhibitor to FUT-175, and levels of cleaved caspase-8 were increased by inhibition of GSK-3. PP2A inhibitor increased the levels of phosphorylated GSK-3? and sensitized both cell lines to FUT-175 as measured by cell viability and apoptotic signal. The results indicate that GSK-3? activity plays a key role in the antitumor effect of FUT-175 in pancreatic cancer cells, and regulation of GSK-3? by PP2A inhibition could be a novel therapeutic approach for pancreatic cancer.

SUBMITTER: Haruki K

PROVIDER: S-EPMC5868870 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Glycogen synthase kinase-3β activity plays a key role in the antitumor effect of nafamostat mesilate in pancreatic cancer cells.

Haruki Koichiro K Shiba Hiroaki H Shimada Yohta Y Shirai Yoshihiro Y Iwase Ryota R Fujiwara Yuki Y Uwagawa Tadashi T Ohashi Toya T Yanaga Katsuhiko K

Annals of gastroenterological surgery 20170831 1

Pancreatic cancer is often resistant to chemotherapy. We previously showed the efficacy of combination treatment using gemcitabine and nafamostat mesilate (FUT-175) for patients with unresectable pancreatic cancer. However, the mechanisms that affect the sensitivity of FUT-175 are not fully understood. The purpose of the present study was to clarify the mechanism of the sensitivity to FUT-175, with a focus on the activity of glycogen synthase kinase-3β (GSK-3β). In vitro, we assessed sensitivity ...[more]

PMID: 29863120

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Project description:Soluble cell adhesion molecules (sCAMs) are secreted ectodomain fragments of surface adhesion molecules, ICAM1 and VCAM1. sCAMs have diverse immune functions beyond their primary function, impacting immune cell recruitment and activation. Elevated sVCAM1 levels have been found to be associated with poor cardiovascular disease (CVD) outcomes, supporting VCAM1's role as a potential diagnostic marker and therapeutic target. Inhibiting sVCAM1's release or its interaction with immune cells could offer cardioprotection in conditions such as diabetes. Membrane-bound surface adhesion molecules are widely expressed in a wide variety of cell types with higher expression in endothelial cells (ECs). Still, the source of sCAMs in the circulation is not clear. Hypothesizing that endothelial cells (ECs) could be a potential source of sCAMs, this study investigated whether dysfunctional EC signaling mechanisms during diabetes cause VCAM1 ectodomain shedding. Our results from samples from an inducible diabetic mouse model revealed increased sVCAM1 plasma levels in diabetes. Protein analysis indicated upregulated VCAM1 expression and metalloproteases ADAM10 and ADAM17 in diabetic ECs. ADAMs are known for proteolytic cleavage of adhesion molecules, contributing to inflammation. GSK3β, implicated in EC VCAM1 expression, was found to be activated in diabetic ECs. GSK3β activation in control ECs increased ADAM10/17 and VCAM1. A GSK3β inhibitor reduced active GSK3β and VCAM1 ectodomain shedding. These findings suggest diabetic ECs with elevated GSK3β activity led to VCAM1 upregulation and ADAM10/17-mediated sVCAM1 shedding. This mechanism underscores the potential therapeutic role of GSK3β inhibition in reducing the levels of circulating sVCAM1. The complex roles of sCAMs extend well beyond CVD. Thus, unraveling the intricate involvement of sCAMs in the initiation and progression of vascular disease, particularly in diabetes, holds significant therapeutic potential.

Dataset Information

Glycogen synthase kinase-3? activity plays a key role in the antitumor effect of nafamostat mesilate in pancreatic cancer cells.

Publications

Glycogen synthase kinase-3β activity plays a key role in the antitumor effect of nafamostat mesilate in pancreatic cancer cells.

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