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Cordycepin inhibits lipopolysaccharide-induced cell migration and invasion in human colorectal carcinoma HCT-116 cells through down-regulation of prostaglandin E2 receptor EP4.

ABSTRACT: Prostaglandin E2 (PGE2), a major product of cyclooxygenase-2 (COX-2), plays an important role in the carcinogenesis of many solid tumors, including colorectal cancer. Because PGE2 functions by signaling through PGE2 receptors (EPs), which regulate tumor cell growth, invasion, and migration, there has been a growing amount of interest in the therapeutic potential of targeting EPs. In the present study, we investigated the role of EP4 on the effectiveness of cordycepin in inhibiting the migration and invasion of HCT116 human colorectal carcinoma cells. Our data indicate that cordycepin suppressed lipopolysaccharide (LPS)-enhanced cell migration and invasion through the inactivation of matrix metalloproteinase (MMP)-9 as well as the down-regulation of COX-2 expression and PGE2 production. These events were shown to be associated with the inactivation of EP4 and activation of AMP-activated protein kinase (AMPK). Moreover, the EP4 antagonist AH23848 prevented LPS-induced MMP-9 expression and cell invasion in HCT116 cells. However, the AMPK inhibitor, compound C, as well as AMPK knockdown via siRNA, attenuated the cordycepin-induced inhibition of EP4 expression. Cordycepin treatment also reduced the activation of CREB. These findings indicate that cordycepin suppresses the migration and invasion of HCT116 cells through modulating EP4 expression and the AMPK-CREB signaling pathway. Therefore, cordycepin has the potential to serve as a potent anti-cancer agent in therapeutic strategies against colorectal cancer metastasis. [BMB Reports 2018; 51(10): 533-538].

SUBMITTER: Jeong JW

PROVIDER: S-EPMC6235086 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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Cordycepin inhibits lipopolysaccharide-induced cell migration and invasion in human colorectal carcinoma HCT-116 cells through down-regulation of prostaglandin E2 receptor EP4.

Jeong Jin-Woo JW Park Cheol C Cha Hee-Jae HJ Hong Su Hyun SH Park Shin-Hyung SH Kim Gi-Young GY Kim Woo Jean WJ Kim Cheol Hong CH Song Kyoung Seob KS Choi Yung Hyun YH

BMB reports 20181001 10

Prostaglandin E2 (PGE2), a major product of cyclooxygenase-2 (COX-2), plays an important role in the carcinogenesis of many solid tumors, including colorectal cancer. Because PGE2 functions by signaling through PGE2 receptors (EPs), which regulate tumor cell growth, invasion, and migration, there has been a growing amount of interest in the therapeutic potential of targeting EPs. In the present study, we investigated the role of EP4 on the effectiveness of cordycepin in inhibiting the migration ...[more]

PMID: 30269738

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Project description:With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist-treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle-treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator-activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator-activated receptor ? activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus.

Project description:Background & Aims Infection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E2 is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE2 signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction. Methods Using samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE2 and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function. We performed western blotting and immunohistochemistry for PG biosynthetic machinery expression in liver tissue. Finally, we investigated the effect of PGE2 antagonists in whole blood using polychromatic flow cytometry and cytokine production. Results We show that hepatic production of PGE2 via the cyclo-oxygenase 1–microsomal PGE synthase 1 pathway, and circulating monocytes contributes to increased plasma PGE2 in decompensated cirrhosis. Transjugular intrahepatic sampling did not reveal whether hepatic or monocytic production was larger. Blood monocyte numbers increased, whereas individual monocyte function decreased as patients progressed from outpatients with ascites to patients hospitalised with acute decompensation, as assessed by Human Leukocyte Antigen (HLA)–DR isotype expression and tumour necrosis factor alpha and IL6 production. PGE2 mediated this dysfunction via its EP4 receptor. Conclusions PGE2 mediates monocyte dysfunction in decompensated cirrhosis via its EP4 receptor and dysfunction was worse in hospitalised patients compared with outpatients with ascites. Our study identifies a potential drug target and therapeutic opportunity in these outpatients with ascites to reverse this process to prevent infection and hospital admission. Lay summary Patients with decompensated cirrhosis (jaundice, fluid build-up, confusion, and vomiting blood) have high infection rates that lead to high mortality rates. A white blood cell subset, monocytes, function poorly in these patients, which is a key factor underlying their sensitivity to infection. We show that monocyte dysfunction in decompensated cirrhosis is mediated by a lipid hormone in the blood, prostaglandin E2, which is present at elevated levels, via its EP4 pathway. This dysfunction worsens when patients are hospitalised with complications of cirrhosis compared with those in the outpatients setting, which supports the EP4 pathway as a potential therapeutic target for patients to prevent infection and hospitalisation. Graphical abstract Highlights • We demonstrate that monocyte dysfunction in patients with decompensated cirrhosis and refractory ascites is mediated by PGE2 through its EP4 receptor.• Monocyte HLA-DR expression was also reduced in both cohorts of patients with decompensated cirrhosis, at least in part, by elevated circulating PGE2.• Up to 55% of patients with ACLF have an infective precipitant.• Improving monocyte function in patients with pre-hospital cirrhosis and ascites could prevent development of ACLF.• PGE2-EP4 receptor antagonists might represent a treatment to improve monocyte dysfunction in outpatients with ascites.

Dataset Information

Cordycepin inhibits lipopolysaccharide-induced cell migration and invasion in human colorectal carcinoma HCT-116 cells through down-regulation of prostaglandin E2 receptor EP4.

Publications

Cordycepin inhibits lipopolysaccharide-induced cell migration and invasion in human colorectal carcinoma HCT-116 cells through down-regulation of prostaglandin E2 receptor EP4.

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