Prostaglandin E2-stimulated prostanoid EP4 receptors induce prolonged de novo prostaglandin E2 synthesis through biphasic phosphorylation of extracellular signal-regulated kinases mediated by activation of protein kinase A in HCA-7 human colon cancer cells

Fujino, Hiromichi; Seira, Naofumi; Kurata, Nori; Araki, Yoshinori; Nakamura, Hiroyuki; Regan, John W.; Murayama, Toshihiko

doi:10.1016/j.ejphar.2015.10.044

Cited by 14 publications

(11 citation statements)

References 30 publications

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“…A significant increase in proliferation of Ishikawa cells was observed under PGE2 stimulation (1 × 10 −9 mol/L), which was abolished in shPTGE2-Ishikawa cells (Fig 2e). The PGE2 concentrations used here were similar as in previously reported studies [21, 22]. Additionally, PGE2 also increased the invasion of Ishikawa cells (Fig.…”

Section: Resultssupporting

confidence: 89%

Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer

Yao

Che

et al. 2016

Tumor Biol.

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Prostaglandin E2 (PGE2), a derivative of arachidonic acid, has been identified as a tumorigenic factor in many cancers in recent studies. Prostaglandin E synthase 2 (PTGES2) is an enzyme that in humans is encoded by the PTGES2 gene located on chromosome 9, and it synthesizes PGE2 in human cells. In our study, we selected 119 samples from endometrial cancer patients, with 50 normal endometrium tissue samples as controls, in which we examined the expression of PTGES2. Both immunohistochemistry (IHC) and Western blot analyses demonstrated that synthase PTGES2, which is required for PGE2 synthesis, was highly expressed in endometrium cancer tissues compared with normal endometrium. Stable PTGES2-shRNA transfectants were generated in Ishikawa and Hec-1B endometrial cancer cell lines, and transfection efficiencies were confirmed by RT-PCR and Western blot analyses. We found that PGE2 promoted proliferation and invasion of cells in Ishikawa and Hec-1B cells by cell counting kit-8 tests (CCK8) and transwell assays, respectively. PGE2 stimulation enhanced the expression of SUMO-1, via PGE2 receptor subtype 4 (EP4). Further analysis implicated the Wnt/β-catenin signaling pathway function as the major mediator of EP4 and SUMO-1. The increase in SUMO-1 activity prompted the SUMOlyation of target proteins which may be involved in proliferation and invasion. These findings suggest SUMO-1 and EP4 as two potential targets for new therapeutic or prevention strategies for endometrial cancers.

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Section: Resultssupporting

confidence: 89%

Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer

Yao

Che

et al. 2016

Tumor Biol.

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“…48) Thus, the activation of EP4 receptors by PGE 2 in HCA-7 cells evoked PKA-dependent re-activation of ERKs, which led to prolonged de novo synthesis of PGE 2 plausibly via a mechanism of resensitization involving the poly-alanine residues (five alanines), which are embedded between two PKA consensus phosphorylation sites, serine 222 and serine 259, as described above, 48) of the ICL3 region of EP4 receptors. 49) Meanwhile, direct activation of EGF receptors by EGF also induced similar amounts of COX-2 in this cell line.…”

Section: Brief Sketch Of Findings Using Hca-7 Colon Cancer Cell Systemmentioning

confidence: 99%

“…However, activation of this pathway was transient and not mediated by PKA. 48) As described earlier, HCA-7 cells are possibly the most appropriate cells with which to evaluate the early development stage of colon carcinogenesis, since the cells retain some of the functional features of normal colonic epithelia. 41) Thus, the novel biphasic activation of ERKs followed by prolonged de novo PGE 2 synthesis mediated by PKA activation in EP4 receptor-stimulated signaling provides an insight into the importance of the G s -protein/cAMP/PKA pathway in cancer development and why not EGF but PGE 2 has been linked to an early stage of carcinogenesis, especially in EP4 receptorinduced development of colon cancer.…”

Section: Brief Sketch Of Findings Using Hca-7 Colon Cancer Cell Systemmentioning

confidence: 99%

“…49) Meanwhile, direct activation of EGF receptors by EGF also induced similar amounts of COX-2 in this cell line. 48) Therefore, the effects of EGF-stimulated EGF receptors in HCA-7 cells was also examined and it was found that EGF stimulation also induced COX-2 and de novo synthesis of PGE 2 . However, activation of this pathway was transient and not mediated by PKA.…”

Section: Brief Sketch Of Findings Using Hca-7 Colon Cancer Cell Systemmentioning

confidence: 99%

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The Roles of EP4 Prostanoid Receptors in Cancer Malignancy Signaling

Fujino

2016

Biological & Pharmaceutical Bulletin

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The lipid mediator prostanoids consist of prostaglandins and thromboxanes, and are synthesized from arachidonic acid by the action of cyclooxygenase. There are five major prostanoids, including prostaglandin E 2 (PGE 2 ), and they are involved in a variety of biological responses such as inflammation, allergy, parturition, and tumorigenesis. These prostanoids exert their effects via activation of their cognate G protein coupled receptors, e.g., E-type prostanoid (EP) receptors for PGE 2 . The EP receptors are composed of four subtypes, namely EP1 to EP4. Here, breakthroughs in the last dozen years of research are introduced, with a special focus on some important findings of EP4 receptor-mediated signaling and the signaling associated with cancer development, particularly in colon cancer.

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“…Among them, EP4 receptor-mediated signaling has been extensively studied because it is known to be involved in colon cancer malignancy [5][6][7]. Thus, COX-2 expression and the de novo synthesis of PGE 2 are induced by the activation of EP4 receptors through G ai -proteinmediated signaling in HCA-7 human colon cancer cells [8,9]. Another hallmark of colorectal carcinogenesis is an increase in T-cell factor (TCF)/b-catenin (b-cat) transcriptional activity [10], which is also primarily regulated by the G ai -protein-mediated pathway of EP4 receptors [7,11].…”

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PGE₁ and E₃ show lower efficacies than E₂ to β‐catenin‐mediated activity as biased ligands of EP4 prostanoid receptors

et al. 2017

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The 2-series of prostaglandin E (PGE ) is regarded as a pro-cancer prostanoid, whereas the 1-series (PGE ) and the 3-series (PGE ) are considered to act as anti-cancer prostanoids. In the present study, we provide possible reasons why PGE and PGE , but not PGE , exert anti-cancer effects by focusing on each diverged E-type prostanoid (EP)4 receptor-mediated signaling pathway. PGE , PGE and PGE function as full agonists in terms of G - and G -protein-mediated signaling. However, PGE and PGE function as partial agonists of T-cell factor (TCF)/β-catenin (β-cat)-mediated activity, the well-known cancer-related signaling pathway. Furthermore, pretreatment with PGE or PGE almost completely reduces PGE -induced TCF/β-cat activity. These results provide a plausible reason why PGE and PGE function as anti-cancer prostanoids as a result of novel biased activity for EP4 receptors.

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Prostaglandin E2-stimulated prostanoid EP4 receptors induce prolonged de novo prostaglandin E2 synthesis through biphasic phosphorylation of extracellular signal-regulated kinases mediated by activation of protein kinase A in HCA-7 human colon cancer cells

Cited by 14 publications

References 30 publications

Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer

Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer

The Roles of EP4 Prostanoid Receptors in Cancer Malignancy Signaling

PGE₁ and E₃ show lower efficacies than E₂ to β‐catenin‐mediated activity as biased ligands of EP4 prostanoid receptors

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Prostaglandin E2-stimulated prostanoid EP4 receptors induce prolonged de novo prostaglandin E2 synthesis through biphasic phosphorylation of extracellular signal-regulated kinases mediated by activation of protein kinase A in HCA-7 human colon cancer cells

Cited by 14 publications

References 30 publications

Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer

Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer

The Roles of EP4 Prostanoid Receptors in Cancer Malignancy Signaling

PGE1 and E3 show lower efficacies than E2 to β‐catenin‐mediated activity as biased ligands of EP4 prostanoid receptors

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PGE₁ and E₃ show lower efficacies than E₂ to β‐catenin‐mediated activity as biased ligands of EP4 prostanoid receptors