内毒素诱导非小细胞肺癌细胞增殖及其机制

目的：研究内毒素对体外培养非小细胞肺癌（NSCLC）细胞株A549细胞增殖的影响及其机制。方法：不同浓度脂多糖（LPS）进行8-48h干预,MTT及细胞计数法检测其对A549细胞增殖的影响;EGFR中和抗体或COX．2抑制剂与LPS联合干预,检测其对A549细胞增殖及PGE2的影响。结果iLPS可引发A549细胞MTT活性和细胞计数显著增加,且呈现时间和剂量依赖性。LPS还可诱发PGE2水平显著升高。药物干预结果显示,抑制COX-2或EGFR可明显逆转LPS所引发的细胞增殖和PGE2水平升高趋势。结论：LPS可能通过激活EGFR和COX-2信号途径,诱导体外培养的非小细胞肺癌细胞增殖分化。肺部感染可能会加速非小细胞肺癌进展,并可能造成不良预后。     

紫铆因靶向EGFR和AuroraA/B信号通路抑制非小细胞肺癌的研究

紫铆因抗多种肿瘤的生物学活性已被广泛研究,但其抑制非小细胞肺癌(non-small cell lung cancer,NSCLC)的分子机制还不清楚。研究中,通过MTS和软琼脂集落实验检测紫铆因对非小细胞肺癌细胞停泊依赖和停泊非依赖增殖的影响,利用免疫印迹检测紫铆因处理后非小细胞肺癌表皮生长因子受体(epidermal growth factor receptor,EGFR)信号通路的磷酸化状态,同时采用流式细胞术检测紫铆因对非小细胞肺癌细胞周期演进的影响。研究发现紫铆因剂量依赖性抑制A549和H1650细胞增殖,在抑制EGFR信号通路磷酸化活化的同时下调EGFR总蛋白及EGFR在胞膜和胞核的表达,而且紫铆因下调AuroraA/B和H3-S10磷酸化,促进A549细胞G2/M期阻滞。结果表明紫铆因可通过靶向EGFR和AuroraA/B信号通路抑制非小细胞肺癌。     

EGCG对LPS刺激人肺腺癌A549细胞凋亡及CUGBP1蛋白表达的影响

目的：研究表没食子儿茶素-3-没食子酸酯（epigallocatechin-3-gallate,EGCG）对炎性刺激的人肺腺癌A549细胞增殖和凋亡的影响及与CUGBP1表达的关系。方法：MTT法检测EGCG和LPS刺激A549细胞增殖活性的影响;流式细胞仪检测细胞凋亡;免疫细胞化学检测EGCG对LPS刺激人肺腺癌A549细胞内CUGBP1蛋白的表达。结果：与对照组相比,LPS体外显著促进A549细胞增殖,其胞核胞质内CUGBP1表达明显增强（P〈0.01）。加入EGCG可拮抗LPS促A549细胞增殖的作用,促进其凋亡,明显抑制LPS刺激的A549细胞内CUGBP1的表达（P〈0.01）。CUGBP1蛋白定量分析可知EGCG和LPS共同孵育A549细胞4h、24h时,细胞中的CUGBP1蛋白表达量较单纯LPS作用时降低。但EGCG和LPS共同孵育A549细胞24h,A549细胞中胞核CUGBP1蛋白表达量（1210.565±3.46）较4h时胞核CUGBP1蛋白表达量（67.344±3.68）高,差异有统计学意义（t=927.164,P〈0.001）。结论：EGCG可能通过干扰CUGBP1基因的表达抑制炎症刺激人肺腺癌细胞A549的增殖,促进其凋亡。     

Prohibitin对非小细胞肺癌细胞增殖和凋亡的影响

目的:研究Prohibitin对非小细胞肺癌株A549和NCI-H460细胞增殖和凋亡的影响.方法:将针对Prohibitin的特异性的干扰片段瞬时转染非小细胞肺癌A549和NCI-H460细胞株,以瞬时转染与Prohibitin没有同源性的干扰片段的细胞作为阴性对照,通过免疫蛋白印迹检测各组细胞Prohibitin和Survivin蛋白的表达情况,通过MTT法检测各组细胞的增殖情况,通过流式仪检测各组细胞的凋亡率.结果:针对Prohibitin基因设计的siRNA片段特异性地沉默该基因的表达,与对照组相比较,干扰组的细胞的增殖活性明显增强.同时与凋亡密切相关的Survivin的表达在沉默掉prohibitin后,在A549和NCI-H460中分别降低了46.3%和54.5%.而干扰prohibitin后导致A549细胞的凋亡率上升了约2%.结论:Prohibitin能显著抑制非小细胞肺癌A549和NCI-H460细胞的增殖,而对凋亡的影响可能并不是通过survivin介导的.     

IQGAP1通过ERK信号通路促进非小细胞肺癌细胞增殖

该研究探讨了IQGAP1(IQ domain GTPase-activating protein 1)对非小细胞肺癌(nonsmall cell lung cancer,NSCLC)细胞增殖的影响及其对ERK信号通路的调节作用。将内源性IQGAP1低表达的A549细胞中分为空白组、空载组和IQGAP1过表达组;将内源性IQGAP1高表达的H1299细胞中分为空白组、阴性对照si RNA组和IQGAP1 si RNA组;采用ERK1/2磷酸化抑制剂U0126处理上述两株细胞。MTT法检测细胞增殖能力,Western blot法检测ERK1/2和p-ERK1/2蛋白质水平。结果显示,在A549细胞中,过表达IQGAP1能促进细胞增殖并促进ERK1/2磷酸化;在H1299中,敲低IQGAP1表达能够抑制细胞增殖并下调ERK1/2磷酸化水平。用U0126处理后能抑制IQGAP1对细胞增殖的促进作用。研究结果表明,IQGAP1可通过ERK信号通路促进体外非小细胞肺癌细胞增殖。     

香鳞毛蕨苷提取物E对人肺癌A549细胞增殖及凋亡的影响

目的:研究香鳞毛蕨苷提取物E(Fragranoside E)对人肺癌A549细胞增殖及凋亡的影响。方法:将体外培养的人肺癌A549细胞分为对照组(0.1%DMSO、100 nM紫杉醇)和实验组,通过CCK-8实验、克隆形成实验检测细胞增殖情况;检测乳酸脱氢酶(LDH)水平以探讨Fragranoside E的细胞毒性;透射电镜及流式细胞术检测A549细胞的凋亡情况。进一步采用5mM N-乙酰半胱氨酸(N-acetylcysteine,NAC)预处理A549细胞2 h后,采用荧光显微镜观察细胞内ROS的释放情况。结果:CCK8及克隆形成实验结果提示Fragranoside E呈浓度和时间依赖性抑制A549细胞增殖(P0.05);≤40μM Fragranoside E处理A549细胞对其LDH的释放无显著影响(P0.05);而40μM Fragranoside E可诱导A549细胞凋亡,细胞内ROS升高,NAC(5 m M)预处理2 h后,细胞内ROS(112.6%±12.3%)较Fragranoside E处理组显著降低(P0.05)。结论:Fragranoside E能够抑制A549细胞增殖,诱导其凋亡,其抗肿瘤活性可能与细胞内ROS释放有关。     

褪黑素对肺腺癌A549 细胞增殖及核转录因子Bp65 核移位的影响

目的:探讨褪黑素(MLT)对体外培养的肺腺癌A549细胞增殖的影响及作用机制。方法:体外培养人肺腺癌A549细胞,通过不同浓度的褪黑素(0.1、1.0、2.5、5.0mmol/L)干预24、48、72h,通过噻唑蓝(MTT)法测定细胞增殖,DNA末端原位标记染色法(Tunel)检测细胞凋亡情况,蛋白印迹(Western-blot)法检测褪黑素对A549细胞核内核转录因子Bp65(NF-Bp65)蛋白水平的影响。结果:褪黑素能够抑制人肺腺癌A549细胞增殖,呈剂量、时间依赖性性;高浓度褪黑素作用后凋亡细胞比例明显升高,同时细胞核内NF-Bp65蛋白量明显减少。结论:褪黑素能够呈剂量、时间依赖性抑制人肺腺癌A549细胞的增殖,抑制核因子Bp65的核移位诱导细胞凋亡是可能作用路径之一。     

EGCG对LPS刺激人肺腺癌A549细胞凋亡及CUGBP1蛋白表达的影响

目的:研究表没食子儿茶素-3-没食子酸酯(epigallocatechin-3-gallate,EGCG)对炎性刺激的人肺腺癌A549细胞增殖和凋亡的影响及与CUGBP1表达的关系。方法:MTT法检测EGCG和LPS刺激A549细胞增殖活性的影响;流式细胞仪检测细胞凋亡;免疫细胞化学检测EGCG对LPS刺激人肺腺癌A549细胞内CUGBP1蛋白的表达。结果:与对照组相比,LPS体外显著促进A549细胞增殖,其胞核胞质内CUGBP1表达明显增强(P0.01)。加入EGCG可拮抗LPS促A549细胞增殖的作用,促进其凋亡,明显抑制LPS刺激的A549细胞内CUGBP1的表达(P0.01)。CUGBP1蛋白定量分析可知EGCG和LPS共同孵育A549细胞4h、24h时,细胞中的CUGBP1蛋白表达量较单纯LPS作用时降低。但EGCG和LPS共同孵育A549细胞24h,A549细胞中胞核CUGBP1蛋白表达量(1210.565±3.46)较4h时胞核CUGBP1蛋白表达量(67.344±3.68)高,差异有统计学意义(t=927.164,P0.001)。结论:EGCG可能通过干扰CUGBP1基因的表达抑制炎症刺激人肺腺癌细胞A549的增殖,促进其凋亡。     

RGD肽对肺癌A549 细胞增殖侵袭能力的影响及其机制研究

目的:研究RGD肽对肺癌A549细胞增殖凋亡及侵袭迁移的影响,并探讨其作用机制。方法:不同浓度RGD肽处理肺癌A549细胞后,MTT检测肺癌细胞的增殖能力,流式细胞仪检测肺癌细胞凋亡及周期分布,Transwell检测其迁移及侵袭能力的变化,Western blot检测RGD肽对肺癌A549细胞MMP2、MMP9的表达水平影响。结果:当RGD肽浓度增加至50 mg/L时,肺癌A549细胞增殖明显受到抑制,且这种抑制作用呈剂量依赖关系;RGD肽组A549细胞G0/G1期细胞比例增高,细胞凋亡率由(6.1±0.1)%增至(15.2±0.5)%;在迁移和侵袭试验中,RGD肽组A549细胞的穿膜细胞数分别由123±10和43±10降至45±5和18±5;RGD肽组A549细胞MMP2、MMP9表达水平显著降低。结论:RGD肽对肺癌A549细胞的增殖有明显抑制作用,并促进其凋亡,可能与RGD肽改变其周期分布有关,RGD肽可明显抑制A549细胞的迁移及侵袭,可能与其下调MMP2、MMP9的表达相关。     

NOK过表达对肺腺癌细胞A549增殖的影响

目的:本研究通过建立稳定过表达NOK基因的A549-NOK细胞系观察其增殖变化,探讨NOK基因对A549增殖的影响。方法:运用电穿孔仪将pcDNA3.1-NOK质粒转染人肺癌A549细胞,筛选出稳定过表达NOK基因的单克隆株A549-NOK。RT-PCR检测转染前后细胞内NOK基因的表达效果。通过流式细胞术检测细胞周期,MTT法绘制细胞生长曲线。结果:RT-PCR显示A549-NOK细胞中NOK基因表达量明显增高。流式细胞术显示A549-NOK与A549、空质粒对照组细胞相比,S期细胞增多(51.7±2.2 vs 43.4±1.5,45.7±1.4,均P0.05);细胞增殖指数升高(69.4±1.1vs 58.4±1.3,57.9±1.4,均P0.05);MTT结果显示A549-NOK细胞较A549和空质粒对照组细胞生长曲线上移。结论:NOK可促进A549细胞的增殖,可能在肺癌的发生、发展中发挥重要作用。     

Endotoxin induces proliferation of NSCLC in vitro and in vivo: role of COX-2 and EGFR activation

Lung cancer is frequently complicated by pulmonary infections which may impair prognosis of this disease. Therefore, we investigated the effect of bacterial lipopolysaccharides (LPS) on tumor proliferation in vitro in the non-small cell lung cancer (NSCLC) cell line A549, ex vivo in a tissue culture model using human NSCLC specimens and in vivo in the A549 adenocarcinoma mouse model. LPS induced a time- and dose-dependent increase in proliferation of A549 cells as quantified by MTS activity and cell counting. In parallel, an increased expression of the proliferation marker Ki-67 and cyclooxygenase (COX)-2 was detected both in A549 cells and in ex vivo human NSCLC tissue. Large amounts of COX-2-derived prostaglandin (PG)E₂ were secreted from LPS-stimulated A549 cells. Pharmacological interventions revealed that the proliferative effect of LPS was dependent on CD14 and Toll-like receptor (TLR)4. Moreover, blocking of the epidermal growth factor receptor (EGFR) also decreased LPS-induced proliferation of A549 cells. Inhibition of COX-2 activity in A549 cells severely attenuated both PGE₂ release and proliferation in response to LPS. Synthesis of PGE₂ was also reduced by inhibiting CD14, TLR4 and EGFR in A549 cells. The proliferative effect of LPS on A549 cells could be reproduced in the A549 adenocarcinoma mouse model with enhancement of tumor growth and Ki-67 expression in implanted tumors. In summary, LPS induces proliferation of NSCLC cells in vitro, ex vivo in human NSCLC specimen and in vivo in a mouse model of NSCLC. Pulmonary infection may thus directly induce tumor progression in NSCLC.     

Formation and antiproliferative effect of prostaglandin E(3) from eicosapentaenoic acid in human lung cancer cells

We investigated the formation and pharmacology of prostaglandin E(3) (PGE(3)) derived from fish oil eicosapentaenoic acid (EPA) in human lung cancer A549 cells. Exposure of A549 cells to EPA resulted in the rapid formation and export of PGE(3.) The extracellular ratio of PGE(3) to PGE(2) increased from 0.08 in control cells to 0.8 in cells exposed to EPA within 48 h. Incubation of EPA with cloned ovine or human recombinant cyclooxygenase 2 (COX-2) resulted in 13- and 18-fold greater formation of PGE(3), respectively, than that produced by COX-1. Exposure of A549 cells to 1 microM PGE(3) inhibited cell proliferation by 37.1% (P < 0.05). Exposure of normal human bronchial epithelial (NHBE) cells to PGE(3), however, had no effect. When A549 cells were exposed to EPA (25 microM) or a combination of EPA and celecoxib (a selective COX-2 inhibitor), the inhibitory effect of EPA on the growth of A549 cells was reversed by the presence of celecoxib (at both 5 and 10 microM). This effect appears to be associated with a 50% reduction of PGE(3) formation in cells treated with a combination of EPA and celecoxib compared with cells exposed to EPA alone. These data indicate that exposure of lung cancer cells to EPA results in a decrease in the COX-2-mediated formation of PGE(2), an increase in the level of PGE(3), and PGE(3)-mediated inhibition of tumor cell proliferation.     

Adenosine triphosphate regulates NADPH oxidase activity leading to hydrogen peroxide production and COX-2/PGE2 expression in A549 cells

Non-small cell lung carcinoma (NSCLC) accounts for most of all lung cancers, which is the leading cause of mortality in human beings. High level of cyclooxygenase-2 (COX-2) is one of the features of NSCLC and related to the low survival rate of NSCLC. However, whether extracellular nucleotides releasing from stressed resident tissues contributes to the expression of COX-2 remains unclear. Here, we showed that stimulation of A549 cells by adenosine 5'-O-(3-thiotriphosphate) (ATPγS) led to an increase in COX-2 gene expression and prostaglandin E(2) (PGE(2)) synthesis, revealed by Western blotting, RT-PCR, promoter assay, and enzyme-linked immunosorbent assay. In addition, ATPγS induced intracellular reactive oxygen species (ROS) generation through the activation of NADPH oxidase. The increase of ROS level resulted in activation of the c-Src/epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor (NF)-κB cascade. We also found that activated Akt was translocated into the nucleus and recruited with NF-κB and p300 to form a complex. Thus, activation of p300 modulated the acetylation of histone H4 via the NADPH oxidase/c-Src/EGFR/PI3K/Akt/NF-κB cascade stimulated by ATPγS. Our results are the first to show a novel role of NADPH oxidase-dependent Akt/p65/p300 complex formation that plays a key role in regulating COX-2/PGE(2) expression in ATPγS-treated A549 cells. Taken together, we demonstrated that ATPγS stimulated activation of NADPH oxidase, resulting in generation of ROS, which then activated the downstream c-Src/EGFR/PI3K/Akt/NF-κB/p300 cascade to regulate the expression of COX-2 and synthesis of PGE(2) in A549 cells. Understanding the regulation of COX-2 expression and PGE(2) release by ATPγS on A549 cells may provide potential therapeutic targets of NSCLC.     

Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action

Bufalin, a naturally occurring small-molecule compound from Traditional Chinese Medicine (TCM) Chansu showed inhibitory effects against human prostate, hepatocellular, endometrial and ovarian cancer cells, and leukemia cells. However, whether or not bufalin has inhibitory activity against the proliferation of human non–small cell lung cancer (NSCLC) cells is unclear. The aim of this study is to study the effects of bufalin on the proliferation of NSCLC and its molecular mechanisms of action. The cancer cell proliferation was measured by MTT assay. The apoptosis and cell cycle distribution were analyzed by flow cytometry. The protein expressions and phosphorylation in the cancer cells were detected by Western blot analysis. In the present study, we have demonstrated that bufalin suppressed the proliferation of human NSCLC A549 cell line in time- and dose-dependent manners. Bufalin induced the apoptosis and cell cycle arrest by affecting the protein expressions of Bcl-2/Bax, cytochrome c, caspase-3, PARP, p53, p21WAF1, cyclinD1, and COX-2 in A549 cells. In addition, bufalin reduced the protein levels of receptor expressions and/or phosphorylation of VEGFR1, VEGFR2, EGFR and/or c-Met in A549 cells. Furthermore, bufalin inhibited the protein expressions and phosphorylation of Akt, NF-κB, p44/42 MAPK (ERK1/2) and p38 MAPK in A549 cells. Our results suggest that bufalin inhibits the human lung cancer cell proliferation via VEGFR1/VEGFR2/EGFR/c-Met–Akt/p44/42/p38-NF-κB signaling pathways; bufalin may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of human NSCLC.     

Ciglitazone mediates COX-2 dependent suppression of PGE2 in human non-small cell lung cancer cells

BACKGROUND: Cyclooxygenase-2 (COX-2) over-expression and subsequent prostaglandin E2 (PGE2) production are frequently associated with human non-small-cell lung cancer (NSCLC) and are involved in tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. Here, we report that ciglitazone downregulates PGE2 in NSCLC cells. METHODS: PGE2 ELISA assay and COX-2 ELISA assay were performed for measuring PGE2 and COX-2, respectively, in NSCLC. The mRNA level of COX-2 was measured by semi-quantitative RT-PCR. The transient transfection experiments were performed to measure COX-2 and peroxisome proliferator-response element (PPRE) promoter activity in NSCLC. Western blots were unitized to measure PGE synthase (PGES) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) protein expression. RESULTS: COX-2 ELISA assays suggested that ciglitazone-dependent inhibition of PGE2 occurs through the suppression of COX-2. Ciglitazone treatment suppressed COX-2 mRNA expression and COX-2 promoter activity while upregulating PPRE promoter activity. Ciglitazone did not modify the expression of enzymes downstream of COX-2 including PGES and 15-PGDH. Utilization of a dominant-negative PPARgamma showed that the suppression of COX-2 and PGE2 by ciglitazone is mediated via non-PPAR pathways. CONCLUSION: Taken together, our findings suggest that ciglitazone is a negative modulator of COX-2/PGE2 in NSCLC.     

Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer

Blockade of epidermal growth factor receptor (EGFR) activity has been a primary therapeutic target for non-small cell lung cancers (NSCLC). As patients with wild-type EGFR have demonstrated only modest benefit from EGFR tyrosine kinase inhibitors (TKIs), there is a need for additional therapeutic approaches in patients with wild-type EGFR. As a key component of downstream integrin signalling and known receptor cross-talk with EGFR, we hypothesized that targeting focal adhesion kinase (FAK) activity, which has also been shown to correlate with aggressive stage in NSCLC, would lead to enhanced activity of EGFR TKIs. As such, EGFR TKI-resistant NSCLC cells (A549, H1299, H1975) were treated with the EGFR TKI erlotinib and FAK inhibitors (PF-573,228 or PF-562,271) both as single agents and in combination. We determined cell viability, apoptosis and 3-dimensional growth in vitro and assessed tumor growth in vivo. Treatment of EGFR TKI-resistant NSCLC cells with FAK inhibitor alone effectively inhibited cell viability in all cell lines tested; however, its use in combination with the EGFR TKI erlotinib was more effective at reducing cell viability than either treatment alone when tested in both 2- and 3-dimensional assays in vitro, with enhanced benefit seen in A549 cells. This increased efficacy may be due in part to the observed inhibition of Akt phosphorylation when the drugs were used in combination, where again A549 cells demonstrated the most inhibition following treatment with the drug combination. Combining erlotinib with FAK inhibitor was also potent in vivo as evidenced by reduced tumor growth in the A549 mouse xenograft model. We further ascertained that the enhanced sensitivity was irrespective of the LKB1 mutational status. In summary, we demonstrate the effectiveness of combining erlotinib and FAK inhibitors for use in known EGFR wild-type, EGFR TKI resistant cells, with the potential that a subset of cell types, which includes A549, could be particularly sensitive to this combination treatment. As such, further evaluation of this combination therapy is warranted and could prove to be an effective therapeutic approach for patients with inherent EGFR TKI-resistant NSCLC.     

Cyclooxygenase inhibitors not inhibit resting lung cancer A549 cell proliferation

Cyclooxygenase (COX) inhibitors were regarded as anticarcinogenic agents for lung cancer at least partly via PGE2; but these were based on cytokin stimulation experiment on A549 cell. In order to clarify whether COX inhibitors directly inhibit A549 cell, three COX inhibitors, NS398 (selective COX-2 inhibitor), SC560 (selective COX-1 inhibitor), and acetyl salicylic acid (ASA, non-selective COX inhibitor), were studied. NS398, and ASA, can inhibit PGE2 generation via COX-2 inhibition. The viability of A549 cell was assayed by MTT. However, without cytokin stimulation, all the three inhibitors (NS398 0.2-20 microM; SC560 1.0-100 nM; ASA 0.01-1.0 mM) were not able to inhibit A549 cell proliferation, in the other way round, NS398 promoted cell growth. And arachidonic acid (AA) and lipopolysaccharide (LPS) did not disturb the property of its growth. These data suggested that without cytokin stimulation, COX and PGE2 may not be the kernel molecules involved in A549 cell proliferation, and COX inhibitors could not inhibit A549 cell growth directly.     

Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of the epidermal growth factor receptor and Akt

Cyclooxygenase-2 (COX-2)-mediated prostaglandin synthesis has recently been implicated in human cholangiocarcinogenesis. This study was designed to examine the mechanisms by which COX-2-derived prostaglandin E2 (PGE2) regulates cholangiocarcinoma cell growth and invasion. Immunohistochemical analysis revealed elevated expression of COX-2 and the epidermal growth factor (EGF) receptor (EGFR) in human cholangiocarcinoma tissues. Overexpression of COX-2 in a human cholangiocarcinoma cell line (CCLP1) increased tumor cell growth and invasion in vitro and in severe combined immunodeficient mice. Overexpression of COX-2 or treatment with PGE2 or the EP1 receptor agonist ONO-DI-004 induced phosphorylation of EGFR and enhanced tumor cell proliferation and invasion, which were inhibited by the EP1 receptor small interfering RNA or antagonist ONO-8711. Treatment of CCLP1 cells with PGE2 or ONO-DI-004 enhanced binding of EGFR to the EP1 receptor and c-Src. Furthermore, PGE2 or ONO-DI-004 treatment also increased Akt phosphorylation, which was blocked by the EGFR tyrosine kinase inhibitors AG 1478 and PD 153035. These findings reveal that the EP1 receptor transactivated EGFR, thus activating Akt. On the other hand, activation of EGFR by its cognate ligand (EGF) increased COX-2 expression and PGE2 production, whereas blocking PGE2 synthesis or the EP1 receptor inhibited EGF-induced EGFR phosphorylation. This study reveals a novel cross-talk between the EP1 receptor and EGFR signaling that synergistically promotes cancer cell growth and invasion.