Lane Denis, Robert Véronique, Grondin Roxanne, Rancourt Claudine, Piché Alain
Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Canada.
Int J Cancer. 2007 Sep 15;121(6):1227-37. doi: 10.1002/ijc.22840.
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-FLIP(S) 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 siRNA. We further show that the pro-survival effect of ascites can be suppressed by down-regulation of c-FLIP(S). 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.
腹水常见于晚期卵巢癌患者，富含细胞成分和生长促进因子。本研究旨在评估恶性腹水对TRAIL诱导的细胞凋亡的影响。我们证明，从晚期卵巢癌女性患者获得的恶性腹水可保护肿瘤细胞免受TRAIL和FasL诱导的细胞凋亡，但不能抵抗顺铂诱导的细胞凋亡。在不同的恶性腹水中均一致发现这种抗凋亡作用，而非恶性腹腔积液或来自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激活和PARP裂解。此外，腹水激活PI3K及其下游靶点Akt，并增加c-FLIP(S)蛋白水平，而不影响ERK磷酸化状态。用LY294002抑制PI3K、Akt特异性抑制剂和Akt siRNA可消除恶性腹水的抗凋亡作用。我们进一步表明，下调c-FLIP(S)可抑制腹水的促生存作用。我们的数据表明，恶性积液通过激活PI3K/Akt途径来保护细胞免受TRAIL诱导的细胞凋亡。这些发现表明，肿瘤微环境可能导致卵巢癌细胞对死亡受体诱导的细胞凋亡产生抗性。
