Cytosolic phospholipase A2: targeting cancer through the tumor vasculature.
Cytosolic phospholipase A2: targeting cancer through the tumor vasculature.
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DOI：
10.1158/1078-0432.ccr-08-1905
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发表时间：
2009-03-01
期刊：
影响因子：
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通讯作者：
Yazlovitskaya EM
中科院分区：
文献类型：
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作者：
Linkous A;Geng L;Lyshchik A;Hallahan DE;Yazlovitskaya EM
在血管内皮细胞中，低剂量电离辐射触发胞质磷脂酶A2（cPLA 2）的立即激活。该事件启动促存活信号传导，这可能是肿瘤脉管系统的放射抗性的原因。因此，针对这些生存途径的放射增敏剂的发展可能会增强肿瘤对放射治疗的反应。花生四烯基三氟甲基酮（AACOCF 3）是一种特异性的cPLA 2抑制剂，被研究为潜在的放射增敏剂。血管内皮细胞（3B 11和MPVEC）和肺肿瘤细胞（LLC和H460）在照射前用1μM AACOCF 3处理30分钟。通过克隆形成存活率、ERK 1/2活化、小管形成和迁移试验评价治疗反应。对于体内实验，在照射前30分钟每天施用10 mg/kg AACOCF 3，连续5天处理后肢中具有LLC或H460肿瘤的小鼠。通过肿瘤生长延迟、能量多普勒超声和免疫组织化学评估治疗反应。在细胞培养实验中，用AACOCF 3抑制cPLA 2可防止辐射诱导的ERK 1/2活化，并降低辐射血管内皮细胞的克隆形成存活率，但对肺肿瘤细胞无影响。用AACOCF 3处理也减弱了辐射的血管内皮细胞中的小管形成和迁移。在两种肿瘤小鼠模型中，在照射之前用AACOCF 3处理显著抑制肿瘤生长并降低总体肿瘤血流量和血管分布。肿瘤细胞和肿瘤血管内皮细胞的凋亡增加被确定为所观察到的作用的可能机制。这些发现将cPLA 2鉴定为通过肿瘤脉管系统对放射疗法进行肿瘤敏化的新型分子靶标。
In vascular endothelial cells, low doses of ionizing radiation trigger the immediate activation of cytosolic phospholipase A2 (cPLA2). This event initiates pro-survival signaling which could be responsible for radioresistance of tumor vasculature. Thus, the development of radiosensitizers targeting these survival pathways may enhance tumor response to radiation therapy. Arachidonyltrifluoromethyl Ketone (AACOCF3), a specific cPLA2 inhibitor, was studied as a potential radiosensitizer. Vascular endothelial cells (3B11 and MPVEC) and lung tumor cells (LLC and H460) were treated with 1μM AACOCF3 for 30 minutes prior to irradiation. Treatment response was evaluated by clonogenic survival, activation of ERK1/2, tubule formation and migration assays. For in vivo experiments, mice with LLC or H460 tumors in the hind limbs were treated for 5 consecutive days with 10 mg/kg AACOCF3 administered daily 30 minutes prior to irradiation. Treatment response was assessed by tumor growth delay, Power Doppler Sonography and immunohistochemistry. In cell culture experiments, inhibition of cPLA2 with AACOCF3 prevented radiation-induced activation of ERK1/2 and decreased clonogenic survival of irradiated vascular endothelial cells but not the lung tumor cells. Treatment with AACOCF3 also attenuated tubule formation and migration in irradiated vascular endothelial cells. In both tumor mouse models, treatment with AACOCF3 prior to irradiation significantly suppressed tumor growth and decreased overall tumor blood flow and vascularity. Increased apoptosis in both tumor cells and tumor vascular endothelium was determined as a possible mechanism of the observed effect. These findings identify cPLA2 as a novel molecular target for tumor sensitization to radiation therapy through the tumor vasculature.