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Diabetes mellitus stimulates pancreatic cancer growth and epithelial-mesenchymal transition-mediated metastasis via a p38 MAPK pathway.

ABSTRACT: Diabetes mellitus (DM) and its accompanying chronic inflammation promote tumor progression. p38 mitogen-activated protein kinase (MAPK) is an essential kinase for inflammation. The effects of p38 MAPK on epithelial-mesenchymal transition (EMT)-mediated diabetic pancreatic cancer metastasis remain unclear. Here, we demonstrate that p38 MAPK phosphorylation was significantly increased in pancreatic cancer cells treated with high glucose and in pancreatic tumors from diabetic animals. A p38 MAPK inhibitor significantly suppressed the proliferation and invasion of pancreatic cancer cells under high-glucose conditions. Moreover, p38 MAPK inhibition not only significantly decreased both the tumor volume monitored by magnetic resonance imaging and EMT-related metastasis but also increased the survival of diabetic mice bearing pancreatic tumors. Furthermore, the inflammation in diabetic animals bearing pancreatic tumors was also significantly lower after therapy. Collectively, our findings reveal that p38 MAPK inhibitors may provide a novel intervention strategy for diabetic pancreatic cancer treatment.

SUBMITTER: Wang L

PROVIDER: S-EPMC5122409 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Diabetes mellitus stimulates pancreatic cancer growth and epithelial-mesenchymal transition-mediated metastasis via a p38 MAPK pathway.

Wang Lishan L Bai Ying-Ying YY Yang Yang Y Hu Fangfang F Wang Yonghui Y Yu Zeqian Z Cheng Zhangjun Z Zhou Jiahua J

Oncotarget 20160601 25

Diabetes mellitus (DM) and its accompanying chronic inflammation promote tumor progression. p38 mitogen-activated protein kinase (MAPK) is an essential kinase for inflammation. The effects of p38 MAPK on epithelial-mesenchymal transition (EMT)-mediated diabetic pancreatic cancer metastasis remain unclear. Here, we demonstrate that p38 MAPK phosphorylation was significantly increased in pancreatic cancer cells treated with high glucose and in pancreatic tumors from diabetic animals. A p38 MAPK in ...[more]

PMID: 27413117

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Project description:BackgroundEpithelial-mesenchymal transition of tubular epithelial cells, which is characterized by a loss of epithelial cell characteristics and a gain of ECM-producing myofibroblast characteristics, is an essential mechanism that is involved in tubulointerstitial fibrosis, an important component of the renal injury that is associated with diabetic nephropathy. Under diabetic conditions, p38 MAPK activation has been reported in glomeruli and mesangial cells; however, studies on p38 MAPK in TECs are lacking. In this study, the role of p38 MAPK in AP-1 activation and in the EMT in the human proximal tubular epithelial cell line (HK-2) under high glucose concentration conditions is investigated.Methodology/principal findingsA vector for small interfering RNA that targets p38 MAPK was constructed; the cells were then either transfected with p38 siRNA or pretreated with a chemical inhibitor of AP-1 and incubated with low glucose plus TGF-β1 or high glucose for 48 h. Cells that were not transfected or pretreated and were exposed to low glucose with or without TGF-β1 or high glucose for 48 h were considered to be the controls. We found that high glucose induced an increase in TGF-β1. And high glucose-induced p38 MAPK activation was inhibited by p38 siRNA (P<0.05). A significant decline in E-cadherin and CK expression and a notable increase in vimentin and α-SMA were detected when exposed to low glucose with TGF-β1 or high glucose, and a significant raise of secreted fibronectin were detected when exposed to high glucose; whereas these changes were reversed when the cells were treated with p38 siRNA or AP-1 inhibitor (P<0.05). AP-1 activity levels and Snail expression were up-regulated under high glucose conditions but were markedly down-regulated through knockdown of p38 MAPK with p38 siRNA or pretreatment with AP-1 inhibitor (P<0.05).ConclusionThis study suggests that p38 MAPK may play an important role in the high glucose-induced EMT by activating AP-1 in tubular epithelial cells.

Project description:BackgroundPancreatic cancer is a lethal disease due to the high incidence of metastasis at the time of detection. CD133 expression in clinical pancreatic cancer correlates with poor prognosis and metastasis. However, the molecular mechanism of CD133-regulated metastasis remains unclear. In recent years, epithelial-mesenchymal transition (EMT) has been linked to cancer invasion and metastasis. In the present study we investigated the role of CD133 in pancreatic cancer metastasis and its potential regulatory network.MethodsA highly migratory pancreatic cancer cell line, Capan1M9, was established previously. After shRNA was stable transducted to knock down CD133 in Capan1M9 cells, gene expression was profiled by DNA microarray. Orthotopic, splenic and intravenous transplantation mouse models were set up to examine the tumorigenesis and metastatic capabilities of these cells. In further experiments, real-time RT-PCR, Western blot and co-immunoprecipitate were conducted to evaluate the interactions of CD133, Slug, N-cadherin, ERK1/2 and SRC.ResultsWe found that CD133+ human pancreatic cancer cells were prone to generating metastatic nodules in in vivo models using immunodeficient mice. In contrast, CD133 knockdown suppressed cancer invasion and metastasis in vivo. Gene profiling analysis suggested that CD133 modulated mesenchymal characteristics including the expression of EMT-related genes, such as Slug and N-cadherin. These genes were down-regulated following CD133 knockdown. Moreover, CD133 expression could be modulated by the extracellular signal-regulated kinase (ERK)1/2 and SRC signaling pathways. The binding of CD133 to ERK1/2 and SRC acts as an indispensable mediator of N-cadherin expression.ConclusionsThese results demonstrate that CD133 plays a critical role in facilitating the EMT regulatory loop, specifically by upregulating N-cadherin expression, leading to the invasion and metastasis of pancreatic cancer cells. Our study provides a novel insight into the function of CD133 in the EMT program and a better understanding of the mechanism underlying the involvement of CD133 in pancreatic cancer metastasis.

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Diabetes mellitus stimulates pancreatic cancer growth and epithelial-mesenchymal transition-mediated metastasis via a p38 MAPK pathway.

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Diabetes mellitus stimulates pancreatic cancer growth and epithelial-mesenchymal transition-mediated metastasis via a p38 MAPK pathway.

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