Prostaglandin E2 activates Src signaling in lung adenocarcinoma cell via EP3

Yamaki, Tatsuya; Endoh, Kiyoko; Miyahara, Mituyoshi; Nagamine, Isao; Hương, Nguyêñ Thị Thu; Sakurai, Hiroyuki; Pokorný, Jan; Yano, Tomohiro

doi:10.1016/j.canlet.2004.04.013

Cited by 40 publications

(30 citation statements)

References 21 publications

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“…In contrast, the major signal pathway for the EP3 receptor leads to inhibition of adenylate cyclase via Gi. Different specific patterns of PGE 2 receptor expression has been reported in numerous tumor cell lines and tumor tissues (8)(9)(10)(11)(12). Therefore inconsistent results of research published previously concerning PGE 2 -induced cellular proliferation may have been due to differences in PGE 2 receptor expression among different cell types.…”

Section: Introductioncontrasting

confidence: 46%

Expression of prostaglandin E2 receptors in oral squamous cell carcinomas and growth inhibitory effects of an EP3 selective antagonist, ONO-AE3-240

Hoshikawa¹

2009

Int J Oncol

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Abstract. Prostaglandin E 2 (PGE 2 ) can stimulate tumor progression by both direct and indirect mechanisms. However, its influence on cell proliferation is still unclear. The present study characterized expression of subtypes of PGE 2 receptors in oral squamous cell carcinomas, while also investigating the effects of EP3 and EP4 selective antagonists on oral carcinoma cell lines. EP1, EP2, EP3 and EP4 receptor mRNAs were detected in 4, 5, 10 and 10 of 11 surgical specimens respectively. Application of an EP3 antagonist (ONO-AE3-240) strongly inhibited cell growth in COX-2 and PGE 2 high expression cells (Ca9-22) but not in COX-2 and PGE 2 low expression cells (HSC4). The antagonist also reduced the production of endogenous PGE 2 and induced G0/G1 phase cell arrest. Addition of exogenous PGE 2 only partly abrogated the growth inhibition, indicating that the anti-proliferative effect via EP3 receptor signaling was not only due to PGE 2 -dependent but also PGE 2 -independent mechanisms. In contrast, an EP4 antagonist (ONO-AE3-208) did not inhibit growth in either of the cancer cell lines. In summary, PGE 2 receptor EP3 signaling probably contributes to development of oral carcinomas and use of EP3 antagonist may be a new therapeutic strategy for head and neck cancer.

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Section: Introductioncontrasting

confidence: 46%

Expression of prostaglandin E2 receptors in oral squamous cell carcinomas and growth inhibitory effects of an EP3 selective antagonist, ONO-AE3-240

Hoshikawa¹

2009

Int J Oncol

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“…50 PU.1 expression and activation is controlled by several intracellular signal transduction events, including induction of PI3K/AKT and Src signaling pathways. 51,52 Because these pathways are activated by EP1 and EP3 signaling, 53,54 and because our data identified that PGE 2 regulates Flt3L-dependent DC development through the EP1 and EP3 receptors, it is possible that PGE 2 -mediated induction of PI3K/AKT and Src signaling pathways regulates PU.1 expression in DC-committed progenitors that leads to increased expression of Flt3. However, in other progenitor lineages change in transcription factor activities in the absence of change in expression has been reported.…”

Section: Discussionmentioning

confidence: 91%

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Singh

Hoggatt

et al. 2012

Blood

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Dendritic cell (DC) homeostasis, like all mature blood cells, is maintained via hierarchal generation from hematopoietic precursors; however, little is known about the regulatory mechanisms governing DC generation. Here, we show that prostaglandin E 2 (PGE 2 ) is required for optimal IntroductionDendritic cells (DCs) are specialized Ag-presenting immune cells that induce adaptive immune responses and maintain self-tolerance and are attractive targets for therapeutic manipulation of the immune system. 1,2 Two main DC subsets have been identified on the basis of their location, phenotype, and function: Ag-presenting classic DC (cDC) and type I IFN-producing plasmacytoid DC (pDC), 3,4 and are generated from Flt3-expressing hematopoietic progenitor cells in the BM. 5,6 Recent studies identified a common DC, monocyte and macrophage precursor designated as macrophage DC progenitor cell (MDP) 7,8 and a common DC progenitor (CDP) that is restricted to DC development. 9 MDPs differentiate to CDPs, which in turn give rise to cDCs and pDCs, but not monocytes, and finally to pre-cDCs, 10 a committed precursor of cDCs. 11,12 Unlike MDPs and CDPs that differentiate within the BM, pre-cDCs traffic to secondary lymphoid organs where they further differentiate into cDCs. 4,13 In addition, monocytes can also develop a DC phenotype under inflammatory conditions. 14,15 Flt3 (also known as Flk2 and CD135) is a receptor tyrosine kinase that is broadly expressed on early BM hematopoietic progenitor cells (HPCs), including DC progenitor cells. 5,9,16 Mice with a deficiency in Flt3 or Flt3 ligand (Flt3L) have reduced DC numbers, 13,17 whereas administration of Flt3L dramatically increases BM and peripheral DCs. 18 Although Flt3 signaling is crucial for DC generation from their progenitor cells at steady state, the normal physiologic mechanisms that control Flt3 expression and regulate Flt3L-dependent DC differentiation remain poorly understood.Prostaglandin E 2 (PGE 2 ) is the predominant metabolite of arachidonic acid metabolism produced through the sequential action of phospholipase A 2 , cyclooxygenases (COXs), and PGE synthase. 19,20 There are 2 functionally distinct COX enzyme isoforms, COX1 and COX2, that are encoded by different genes. 20 PGE 2 has been shown to modulate HPC differentiation, inhibiting CFU-GM 21-23 but promoting erythroid burst-forming unit and granulocyte, erythroid, megakaryocyte, and macrophage CFU. 24,25 The long-acting PGE 2 analog, 16,16-dimethyl-PGE 2 (dmPGE 2 ) was shown to increase HSC frequency and engraftment 26,27 and to enhance HSC survival, proliferation, and homing to the BM. 27 Thus, PGE 2 regulates self-renewal and differentiation of HSCs and HPCs, and its effects can differ, depending on hematopoietic cell type and stage of differentiation.The role of PGE 2 in DC maturation and migration under inflammatory conditions is well known. PGE 2 promotes the migration of monocyte-derived and Langerhans DCs, increases their expression of costimulatory molecules, and enhances their ability to stimulate T...

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“…This observation can be supported by results that the treatment reduced the level of Bcl-xL and upregulated Bax via the induction of p53. In our previous study, we reported that PGE 2 induces Bcl-xL due to the activation of Src-signal transducers and activators of transcription 3 [29], but this result indicated that the suppression of PGE 2 production by indomethacin treatment alone was insufficient to reduce the level of Bcl-xL. Similarly, although a previous report suggested that the inhibition of COX by indomethacin is sufficient to induce p53-Bax signaling in cancer cells [30], the inhibition of COX alone in this study could not cause signal induction.…”

Section: Resultsmentioning

confidence: 98%

Peroxisome proliferator‐activated receptor δ as a molecular target to regulate lung cancer cell growth

et al. 2005

Self Cite

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It has been assumed that prostaglandin (PG)I 2 signaling contributes to the negative growth control of lung cancer cells; however, the mechanism remains unresolved. PGI 2 functions through a cell surface G protein-coupled receptor (prostaglandin I2-binding receptor, IP) and also exerts an effect by interacting with a nuclear hormone receptor, peroxisome proliferator-activated receptor d (PPARd). We found that PPARd was a key molecule of PGI 2 signaling to give negative growth control of lung cancer cells (A549), using carbarprostacyclin, a PGI 2 agonist for IP and PPARd, and L-165041, a PPARd agonist. Furthermore, PPARd-induced cell growth control was reinforced by the inhibition of cyclooxygenase. These results suggest that PPARd activation under the suppression of PG synthesis is important to regulate lung cancer cell growth.

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Prostaglandin E2 activates Src signaling in lung adenocarcinoma cell via EP3

Cited by 40 publications

References 21 publications

Expression of prostaglandin E2 receptors in oral squamous cell carcinomas and growth inhibitory effects of an EP3 selective antagonist, ONO-AE3-240

Expression of prostaglandin E2 receptors in oral squamous cell carcinomas and growth inhibitory effects of an EP3 selective antagonist, ONO-AE3-240

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Peroxisome proliferator‐activated receptor δ as a molecular target to regulate lung cancer cell growth

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