Cell detachment modulates TRAIL resistance in ovarian cancer cells by downregulating the phosphatidylinositol 3-kinase/Akt pathway
Cell detachment modulates TRAIL resistance in ovarian cancer cells by downregulating the phosphatidylinositol 3-kinase/Akt pathway
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DOI：
10.1111/j.1525-1438.2007.01062.x
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发表时间：
2008-07-01
影响因子：
4.8
通讯作者：
Piche, A.
中科院分区：
文献类型：
--
作者：
Lane, D.;Cartier, A.;Piche, A.
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）是一种有效的凋亡诱导剂，但许多卵巢癌细胞对TRAIL表现出内在抗性。在这些耐药肿瘤细胞中调节TRAIL敏感性的分子决定因素仍然不完全清楚。我们观察到，在两个TRAIL耐药的卵巢癌细胞系中，细胞脱离增强了TRAIL诱导的凋亡。这一过程伴随着caspase激活的增加，这可以被caspase-8抑制剂IETD阻断。细胞脱离抑制Akt磷酸化。LY 294002对磷脂酰肌醇3激酶的抑制作用也增强了TRAIL诱导的细胞凋亡。LY 294002进一步降低脱附细胞中的Akt活性，导致TRAIL处理后细胞死亡增加。我们的数据表明，细胞脱离增强了TRAIL诱导的杀伤作用，通过降低Akt的活性，在TRAIL耐药的卵巢癌细胞，并建议Akt抑制引物的TRAIL耐药细胞的TRAIL诱导的凋亡。
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potent inducer of apoptosis but many ovarian cancer cells display intrinsic resistance to TRAIL. The molecular determinants regulating TRAIL sensitivity in these resistant tumor cells are still incompletely understood. We observed that cell detachment enhances TRAIL-induced apoptosis in two TRAIL-resistant ovarian cancer cell lines. This process was accompanied by an increase of caspase activation, which could be blocked by caspase-8 inhibitor IETD. Cell detachment inhibited Akt phosphorylation. Phosphatidylinositol 3-kinase inhibition by LY294002 also enhanced TRAIL-induced apoptosis. Further decreased Akt activity by LY294002 in detached cells translated to increased cell death after TRAIL treatment. Our data indicate that cell detachment enhances TRAIL-induced killing by decreasing Akt activity in TRAIL-resistant ovarian carcinoma cells and suggest that Akt inhibition primes TRAIL-resistant cells to TRAIL-induced apoptosis.