Malignant ascites protect against TRAIL-induced apoptosis by activating the PI3K/Akt pathway in human ovarian carcinoma cells
Malignant ascites protect against TRAIL-induced apoptosis by activating the PI3K/Akt pathway in human ovarian carcinoma cells
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DOI：
10.1002/ijc.22840
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发表时间：
2007-09-15
影响因子：
6.4
通讯作者：
Piche, Alain
中科院分区：
文献类型：
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作者：
Lane, Denis;Robert, Veronique;Piche, Alain
腹水常见于晚期卵巢癌患者，富含细胞成分和促生长因子。本研究的目的是评估恶性腹水对TRAIL诱导的细胞凋亡的影响。我们证明，晚期卵巢癌妇女的恶性腹水保护肿瘤细胞免于TRAIL和FasL诱导的凋亡，但不能对抗顺铂诱导的凋亡。这种抗凋亡作用在不同的恶性腹水中一致发现，而非恶性腹膜液或TRAIL抗性细胞的条件培养基未能保护肿瘤细胞免受TRAIL杀伤。恶性腹水强烈抑制TRAIL诱导的caspase-3活化和PARP裂解。此外，腹水激活PI 3 K及其下游靶标Akt并增加c-FLIPS蛋白水平而不影响ERK磷酸化状态。恶性腹水的抗凋亡作用通过用LY 294002抑制PI 3 K、通过Akt的特异性抑制剂和通过Akt ARNA来消除。我们进一步表明，腹水的促生存作用可以通过下调c-FLIPs来抑制。我们的数据表明，恶性积液保护对TRAIL诱导的细胞凋亡，激活PI 3 K/Akt通路。这些发现表明，肿瘤微环境可能有助于卵巢癌细胞对死亡受体诱导的凋亡的抵抗。
Ascites are commonly found in ovarian cancer patients with advanced disease and are rich in cellular components and growth-promoting factors. The purpose of this study was to assess the effect of malignant ascites on TRAIL-induced apoptosis. We demonstrate that malignant ascites obtained from women with advanced ovarian cancer protect tumor cells from TRAIL- and FasL-induced apoptosis but not against cisplatin-induced apoptosis. This antiapoptotic effect was consistently found among different malignant ascites while nonmalignant peritoneal fluids or conditioned medium from TRAIL-resistant cells failed to protect tumor cells against TRAIL killing. Malignant ascites strongly inhibits TRAIL-induced caspase-3 activation and PARP cleavage. Furthermore, ascites activate PI3K and its downstream target Akt and increases c-FLIPS protein levels without affecting ERK phosphorylation status. The antiapoptotic effect of malignant ascites is abrogated by the inhibition of PI3K with LY294002, by a specific inhibitor of Akt and by Akt ARNA. We further show that the prosurvival effect of ascites can be suppressed by down-regulation of c-FLIPs. Our data indicate that malignant effusions protect against TRAIL-induced apoptosis by activating the PI3K/Akt pathway. These findings demonstrate that the tumor microenvironment may contribute to the resistance of ovarian cancer cells to death receptor-induced apoptosis.