Department of Surgery, Division of Cardiothoracic Surgery, University of Colorado School of Medicine, 12631 E. 17th Ave., C302, 80045, Aurora, CO, USA.
Mol Cell Biochem. 2019 Jun;456(1-2):145-156. doi: 10.1007/s11010-019-03500-3. Epub 2019 Jan 25.
Secretory phospholipase A2 IIa (sPLA2 IIa) catalyzes the production of multiple inflammatory mediators that influence the development of lung and other cancers. The most potent of these carcinogenic mediators is prostaglandin E2 (PGE2). We hypothesize that sPLA2 IIa inhibition modulates the production of PGE2, and sPLA2 IIa inhibition exerts its antineoplastic effects via downregulation of PGE2 production. We aim to evaluate these relationships via analysis of PGE2-mediated growth regulation pathways. A549 and H1650 lung adenocarcinoma cells were assayed for PGE2 production in the presence of sPLA2 IIa inhibitor. A549 and H1650 cells were treated with PGE2 and immune blotting was performed to assess ICAM-1 expression and STAT-3 activity. PGE2-induced ICAM-1 expression was measured via immunofluorescence. A549 and H1650 cells were treated with PGE2 in the presence of STAT3 inhibitor and assayed for ICAM-1 expression. A549 cells were treated with PGE2 in the presence ICAM-1 blocking antibody and assayed for invasion. PGE2 stimulation significantly increased the invasiveness and proliferation of lung adenocarcinoma (invasion p < 0.05, proliferation p < 0.05 A549 cells, p < 0.005 H1650 cells). sPLA2 IIa inhibition reduced PGE2 secretion (p < 0.05). PGE2 stimulation significantly upregulated the expression of cell adhesion molecule ICAM-1 and the phosphorylation of anti-apoptotic transcription factor STAT3 (p < 0.05). STAT3 inhibition attenuated ICAM-1 expression demonstrating the dependence of ICAM-1 on the STAT3 pathway (p < 0.05). ICAM-1 blockade attenuated the pro-invasive effects of PGE2 (p < 0.05). sPLA2 IIa inhibition attenuates the potent effects of PGE2-induced invasiveness. This is mediated by decreasing pro-inflammatory and invasion-promoting ICAM-1via the STAT-3 pathway. These data further describe how sPLA2 IIa inhibition mechanistically exerts its anticancer effects and support its use as an antineoplastic agent.
分泌型磷脂酶 A2 IIa（sPLA2 IIa）催化多种炎症介质的产生，这些介质影响肺部和其他癌症的发展。其中最具致癌性的介质是前列腺素 E2（PGE2）。我们假设 sPLA2 IIa 抑制可调节 PGE2 的产生，并且 sPLA2 IIa 抑制通过下调 PGE2 的产生来发挥其抗肿瘤作用。我们旨在通过分析 PGE2 介导的生长调节途径来评估这些关系。在 sPLA2 IIa 抑制剂存在的情况下，检测 A549 和 H1650 肺腺癌细胞中 PGE2 的产生。用 PGE2 处理 A549 和 H1650 细胞，并进行免疫印迹以评估 ICAM-1 表达和 STAT-3 活性。通过免疫荧光测量 PGE2 诱导的 ICAM-1 表达。在 STAT3 抑制剂存在的情况下，用 PGE2 处理 A549 和 H1650 细胞，并检测 ICAM-1 的表达。用 PGE2 处理 A549 细胞，同时用 ICAM-1 阻断抗体处理，并检测侵袭性。PGE2 刺激显著增加了肺腺癌的侵袭性和增殖（侵袭性 p<0.05，增殖 p<0.05 A549 细胞，p<0.005 H1650 细胞）。sPLA2 IIa 抑制减少了 PGE2 的分泌（p<0.05）。PGE2 刺激显著上调细胞黏附分子 ICAM-1 的表达和抗凋亡转录因子 STAT3 的磷酸化（p<0.05）。STAT3 抑制减弱了 ICAM-1 的表达，表明 ICAM-1 依赖于 STAT3 途径（p<0.05）。ICAM-1 阻断减弱了 PGE2 的促侵袭作用（p<0.05）。sPLA2 IIa 抑制减弱了 PGE2 诱导的侵袭性的强烈作用。这是通过减少促炎和促进侵袭的 ICAM-1 来介导的，通过 STAT-3 途径。这些数据进一步描述了 sPLA2 IIa 抑制如何通过机制发挥其抗癌作用，并支持将其用作抗肿瘤剂。
