Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor

Du, Mingzhan; Feng, Suying; Zhang, Hai; Xia, Shukai; Zhang, Min; Ma, Juan; Bai, Xu; Zhang, Li; Wang, Yipin; Cheng, Shanyu; Yang, Qinyi; Leng, Jing

doi:10.3892/or.2015.4043

Cited by 27 publications

(17 citation statements)

References 52 publications

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“…The constitutively active β-catenin signaling pathway results in disturbed cell-to-cell adhesion and consequent upregulation of the migration potential of tumor cells. Moreover, some studies demonstrated that PGE2 could have pro-oncogenic actions including proliferation and metastasis by stimulating β-catenin-mediated transcription in carcinogenesis (22,42). The data presented in the present study provide evidence that meloxicam exerts its anti-migration effects through downregulation of nuclear accumulation of β-catenin and inhibiting the phosphorylation of GSK-3β.…”

Section: Discussionsupporting

confidence: 68%

“…Disturbance of the complex promotes the phosphorylation of β-catenin by glycogen synthase kinase-3β (GSK-3β) and casein kinase 1α (CK1α) leading to the proteasomal degradation of β-catenin (19). β-catenin accumulation eventually leads to its nuclear translocation and then it binds to members of the TCF/LEF family of transcription factors, thus regulating expression of various target genes which are associated with many cellular processes including cell survival, proliferation, and migration (20)(21)(22). Meloxicam (Mel) is an NSAID that specifically inhibits COX-2.…”

Section: Meloxicam Suppresses Hepatocellular Carcinoma Cell Proliferamentioning

confidence: 99%

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Meloxicam suppresses hepatocellular carcinoma cell proliferation and migration by targeting COX-2/PGE2-regulated activation of the β-catenin signaling pathway

Zhong

Dong

et al. 2016

Oncology Reports

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Recurrence and metastasis are the two leading causes of poor prognosis of hepatocellular carcinoma (HCC) patients. Cyclooxygenase (COX)-2 is overexpressed in many types of cancers including HCC and promotes its metastasis. Meloxicam is a selective COX-2 inhibitor that has been reported to exert an anti-proliferation and invasion/migration response in various tumors. In this study, we examined the role of meloxicam on HCC cell proliferation and migration and explored the molecular mechanisms underlying this effect. We found that meloxicam inhibited HCC cell proliferation and had a cell cycle arrest effect in human HCC cells. Furthermore, meloxicam suppressed the ability of HCC cells expressing higher levels of COX-2 and prostaglandin E2 (PGE2) to migration via potentiating expression of E-cadherin and alleviating expression of matrix metalloproteinase (MMP)-2 and -9. COX-2/PGE2 has been considered to activate the β-catenin signaling pathway which promotes cancer cell migration. We found that treatment with PGE2 significantly enhanced nuclear accumulation of β-catenin and the activation of GSK3β which could be reversed by meloxicam in HCC cells. We also observed that HCC cell migration and upregulation of the level of MMP-2/9 and downregulation of E-cadherin induced by PGE2 were suppressed by FH535, an inhibitor of β-catenin. Taken together, these findings provide a new treatment strategy against HCC proliferation and migration.

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Section: Discussionsupporting

confidence: 68%

Section: Meloxicam Suppresses Hepatocellular Carcinoma Cell Proliferamentioning

confidence: 99%

Meloxicam suppresses hepatocellular carcinoma cell proliferation and migration by targeting COX-2/PGE2-regulated activation of the β-catenin signaling pathway

Zhong

Dong

et al. 2016

Oncology Reports

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“…[44][45][46][47][48] β-catenin is an important player in the Wnt signaling pathway and its nuclear translocation results in regulating the expression of various target genes associated cellular processes such as cell survival, proliferation, and migration. 49,50 Our present study revealed that Dsh-003 could block PGE2-induced cell migration effect, finally, and reversed PGE2 induced β-catenin signaling pathway. Therefore, our data indicate that Dsh-003 inhibits PGE2-induced migration effects and β-catenin pathway in HA22T cells.…”

Section: Discussionsupporting

confidence: 54%

“…PGE2 is involved in the β‐catenin pathway and therefore accelerates the progression of cancers of breast, neuroblastoma, hepatocellular carcinoma, and colorectal cancer . β‐catenin is an important player in the Wnt signaling pathway and its nuclear translocation results in regulating the expression of various target genes associated cellular processes such as cell survival, proliferation, and migration . Our present study revealed that Dsh‐003 could block PGE2‐induced cell migration effect, finally, and reversed PGE2 induced β‐catenin signaling pathway.…”

Section: Discussionsupporting

confidence: 52%

Cryptotanshinone (Dsh‐003) from Salvia miltiorrhiza Bunge inhibits prostaglandin E2‐induced survival and invasion effects in HA22T hepatocellular carcinoma cells

Chang

Lin

Shibu

et al. 2018

Environmental Toxicology

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Human hepatocellular carcinoma (HCC) is currently the second most common cancer and one of the leading causes of cancer-related mortality in Taiwan. Previous reports show that the expression of (E-type prostaglandin 2) EP2 and (E-type prostaglandin 4) EP4 are elevated in HCC and further demonstrate that Prostaglandin E2 (PGE2) induces HA22T cell proliferation and metastasis through EP2 and EP4 receptor. Danshen (root of Salvia miltiorrhiza Bunge) is a very important and popular traditional Chinese herbal medicine which is widely and successfully used against breast cancer, leukemia, pancreatic cancer, and head and neck squamous carcinoma cells. In this study, we used Cryptotansinone (Dsh-003) (MW 269.14) from Danshen to investigate their effect and corresponding mechanism of action in PGE2-treated HA22T cells. Dsh-003 inhibited HA22T cell viability and further induced cell apoptosis in PGE2-treated HA22T cells. Furthermore, Dsh-003 inhibited EP2, EP4, and their downstream effector such as p-PI3K and p-Akt expression in HA22T hepatocellular carcinoma cells. We also observed that Dsh-003 blocked PGE2-induced cell migration by down-regulating PGE2-induced β-catenin expression and by up-regulating E-cadherin and GSK3-β expression. All these findings suggest that Dsh-003 inhibit human HCC cell lines and could potentially be used as a novel drug for HCC treatment.

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“…The presence of EP4 and EGFR signaling cross-talk is supported by the fact that inhibition of EGFR reverses the positive effect of EP4 stimulation on matrix degradation, and the other way around. A number of papers proposed the EGFR pathway as effector for EP4-mediated signaling pathways in cancer (Du et al, 2015; Parida et al, 2016; Tveteraas et al, 2012; Yokoyama et al, 2013; M. Zhang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

EP4 receptor promotes invadopodia and invasion in human breast cancer

Tönisen

Perrin

Bayarmagnai

et al. 2017

European Journal of Cell Biology

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The production of Prostaglandin E2 (PGE2) is elevated in human breast cancer cells. The abnormal expression of COX-2, which is involved in the synthesis of PGE2, was recently reported as a critical determinant for invasiveness of human breast cancer cells. Autocrine and paracrine PGE2-mediated stimulation of the PGE2 receptor EP4 transduces multiple signaling pathways leading to diverse patho-physiological effects, including tumor cell invasion and metastasis. It is known that PGE2-induced EP4 activation can transactivate the intracellular signaling pathway of the epidermal growth factor receptor (EGFR). In malignant cancer cells, EGFR pathway activation promotes invadopodia protrusions, which further leads to degradation of the surrounding extracellular matrix (ECM). Despite the known influence of EP4 on the EGFR signaling pathway, the effect of EP4 stimulation on invadopodia formation in human breast cancer was never tested directly. Here we demonstrate the involvement of EP4 in invasion and its effect on invadopodia in breast cancer MDA-MB-231 cells using 2D invadopodia and 3D invasion in vitro assays as well as intravital microscopy. The results show that stimulation with the selective EP4 agonist CAY10598 or PGE2 promotes invadopodia-mediated degradation of the ECM, as well as the invasion of breast cancer cells in in vitro models. The effect on matrix degradation can be abrogated via direct inhibition of EP4 signaling as well as via inhibition of EGFR tyrosine kinase, indicating that EP4-mediated effects on invadopodia-driven degradation are EGFR dependent. Finally, using xenograft mouse models, we show that short-term systemic treatment with CAY10598 results in a >9-fold increase in the number of invadopodia. These findings highlight the importance of further investigation on the role of EP4-EGFR crosstalk in invadopodia formation.

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Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor

Cited by 27 publications

References 52 publications

Meloxicam suppresses hepatocellular carcinoma cell proliferation and migration by targeting COX-2/PGE2-regulated activation of the β-catenin signaling pathway

Meloxicam suppresses hepatocellular carcinoma cell proliferation and migration by targeting COX-2/PGE2-regulated activation of the β-catenin signaling pathway

Cryptotanshinone (Dsh‐003) from Salvia miltiorrhiza Bunge inhibits prostaglandin E2‐induced survival and invasion effects in HA22T hepatocellular carcinoma cells

EP4 receptor promotes invadopodia and invasion in human breast cancer

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