Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth: Involvement of protein kinase C-θ activation

Takahashi, Tetsuyuki; Uehara, Hisanori; Ogawa, Hirohisa; Umemoto, Hitomi; Bando, Yoshimi; Izumi, Kiyotaka

doi:10.18632/oncotarget.3104

Cited by 17 publications

(11 citation statements)

References 42 publications

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“…Our results indicated the critical role of EP4 involved in the effect of solamargine on inhibition of lung cancer cell growth, implying that EP4 could be a potential target in the treatment of lung cancer. Recent studies showed that inhibition of EP4 suppressed growth of several cancer cell types emphasizing the important role of this prostanoid receptor [ 34 , 35 ]. We believed that, as unfavorable tumor-promoting role, EP4 could be a new target in mediating the inhibitory effect of solamargine in lung cancer intervention.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of PI3-K/Akt and reduction of SP1 and p65 expression increase the effect of solamargine on suppressing EP4 expression in human lung cancer cells

Chen

Tang

et al. 2015

J Exp Clin Cancer Res

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BackgroundLung cancer is the most common cause of cancer-related deaths worldwide. Natural phytochemicals from traditional medicinal plants such as solamargine have been shown to have anticancer properties. The prostaglandin E2 receptor EP4 is highly expressed in human cancer, however, the functional role of EP4 in the occurrence and progression of non small cell lung cancer (NSCLC) remained to be elucidated.MethodsCell viability was measured by MTT assays. Western blot was performed to measure the phosphorylation and protein expression of PI3-K downstream effector Akt, transcription factors SP1, p65, and EP4. Quantitative real-time PCR (qRT-PCR) was used to examine the mRNA levels of EP4 gene. Exogenous expression of SP1, p65, and EP4 genes was carried out by transient transfection assays. EP4 promoter activity was measured by Dual Luciferase Reporter Kit.ResultsWe showed that solamargine inhibited the growth of lung cancer cells. Mechanistically, we found that solamargine decreased the phosphorylation of Akt, the protein, mRNA expression, and promoter activity of EP4. Moreover, solamargine inhibited protein expression of SP1 and NF-κB subunit p65, all of which were abrogated in cells transfected with exogenous expressed Akt. Intriguingly, exogenous expressed SP1 overcame the effect of solamargine on inhibition of p65 protein expression, and EP4 protein expression and promoter activity. Finally, exogenous expressed EP4 feedback reversed the effect of solamargine on phosphorylation of Akt and cell growth inhibition.ConclusionOur results show that solamargine inhibits the growth of human lung cancer cells through inactivation of Akt signaling, followed by reduction of SP1 and p65 protein expression. This results in the inhibition of EP4 gene expression. The cross-talk between SP1 and p65, and the positive feedback regulatory loop of PI3-K/Akt signaling by EP4 contribute to the overall responses of solamargine in this process. This study unveils a novel mechanism by which solamargine inhibits growth of human lung cancer cells.

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Section: Discussionmentioning

confidence: 99%

Inactivation of PI3-K/Akt and reduction of SP1 and p65 expression increase the effect of solamargine on suppressing EP4 expression in human lung cancer cells

Chen

Tang

et al. 2015

J Exp Clin Cancer Res

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“…In colorectal cancer, EP4 occupation leads to ERK activation supporting anchorage-independent growth and resistance to apoptosis that is reversed by small molecule EP4 antagonists ONO-AE3-208 and AH23848 (Hawcroft et al, 2007). Likewise, inhibition of the EP2 and EP4 receptors (with AH6809 and GW627368X, respectively) represses IGF-1-induced proliferation of pancreatic BxPC-3 cancer cells (Takahashi et al, 2019) and is accompanied by increased phospho-PKC-q and decreased phospho-ERK (Takahashi et al, 2015).…”

Section: The Role Of Ep4 In Cell Proliferationmentioning

confidence: 99%

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

2020

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The cyclooxygenase-2 (COX-2) enzyme is frequently overexpressed in epithelial malignancies including those of the breast, prostate, lung, kidney, ovary, and liver and elevated expression is associated with worse outcomes. COX-2 catalyzes the metabolism of arachidonic acid to prostaglandins. The COX-2 product prostaglandin E 2 (PGE 2) binds to four G-protein-coupled EP receptors designated EP1-EP4. EP4 is commonly upregulated in cancer and supports cell proliferation, migration, invasion, and metastasis through activation of multiple signaling pathways including ERK, cAMP/PKA, PI3K/AKT, and NF-kB. EP4 antagonists inhibit metastasis in preclinical models. Cancer stem cells, that underlie therapy resistance and disease relapse, are driven by the expression of EP4. Resistance to several chemotherapies is reversed in the presence of EP4 antagonists. In addition to tumor cell-autonomous roles of EP4, many EP4-positive host cells play a role in tumor behavior. Endothelial cell-EP4 supports tumor angiogenesis and lymphangiogenesis. Natural Killer (NK) cells are critical to the mechanism by which systemically administered EP4 antagonists inhibit metastasis. PGE 2 acts on EP4 expressed on the NK cell to inhibit tumor target cell killing, cytokine production, and chemotactic activity. Myeloid-derived suppressor cells (MDSCs), that inhibit the development of cytotoxic T cells, are induced by PGE 2 acting on myeloid-expressed EP2 and EP4 receptors. Inhibition of MDSC-EP4 leads to maturation of effector T cells and suppresses the induction of T regulatory cells. A number of EP4 antagonists have proven useful in dissecting these mechanisms. There is growing evidence that EP4 antagonism, particularly in combination with either chemotherapy, endocrine therapy, or immunebased therapies, should be investigated further as a promising novel approach to cancer therapy. Several EP4 antagonists have now progressed to early phase clinical trials and we eagerly await the results of those studies.

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“…40 EP2 has been demonstrated to promote the activation of ERK signal and promote the formation of pancreatic cancer in mice. 41 More interestingly, our results of Western blot showed that the Akt pathway was significantly activated, not ERK pathway after interfering with the expression of GRK2 in HCC cells by siRNA. The above results suggest that GRK2 may inhibit the invasion and metastasis of HCC by inhibiting the EP2 receptor-mediated Akt signaling pathway.…”

Section: Discussionmentioning

confidence: 72%

<p>GRK2 Suppresses Hepatocellular Carcinoma Metastasis and Invasion Through Down-Regulation of Prostaglandin E Receptor 2</p>

Chen

et al. 2020

OTT

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Background: Hepatocellular carcinoma (HCC) is an aggressive form of human liver cancer and the fifth most common malignancy worldwide. Novel effective treatment strategies for HCC are urgently in clinical because of its poor response to conventional therapies. G protein-coupled receptor kinases (GRKs), including GRK2 and GRK3, are known that involves in various essential cellular processes and regulates numerous signaling pathways. However, the role of GRK2/3 in invasion and metastasis of HCC still remains unclear. Materials and Methods: Immunohistochemistry, Western blot, laser confocal microscopy and qRT-PCR were used to detect the expression of GRK2/3 and EP2 in liver tissues of HCC patients and DEN-induced HCC mice. Wound healing and transwell assay were applied to measure the migration and invasion of HCC cells after transfected with GRK2 siRNA. The downstream pathway of Akt and ERK was verified by Western blot. Results: The expression of GRK2 was significantly decreased, while GRK3 was not significantly changed in HCC tissues compared with noncancerous tissues of HCC patients. Moreover, GRK2 expression was reduced during liver tumorigenesis in diethylnitrosamineinduced liver tumor model. In addition, our in vitro study showed that GRK2 expression was gradually decreased with increasing HCC cell line metastatic potential, and GRK2 knockdown significantly promoted the migration and invasion of HCC cells. Furthermore, low GRK2 expression was associated with increased expression of EP2 receptor translocation to HCC cell membrane, and the activation of Akt pathway. Conclusion: These data suggest that GRK2 inhibits HCC metastasis and invasion may be through regulating EP2 receptor translocation, and this effect appears to be mediated by Akt pathway.

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Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth: Involvement of protein kinase C-θ activation

Cited by 17 publications

References 42 publications

Inactivation of PI3-K/Akt and reduction of SP1 and p65 expression increase the effect of solamargine on suppressing EP4 expression in human lung cancer cells

Inactivation of PI3-K/Akt and reduction of SP1 and p65 expression increase the effect of solamargine on suppressing EP4 expression in human lung cancer cells

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

<p>GRK2 Suppresses Hepatocellular Carcinoma Metastasis and Invasion Through Down-Regulation of Prostaglandin E Receptor 2</p>

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