Lane D, Cartier A, Rancourt C, Piché A
Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Int J Gynecol Cancer. 2008 Jul-Aug;18(4):670-6. doi: 10.1111/j.1525-1438.2007.01062.x. Epub 2007 Sep 14.
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.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种强大的凋亡诱导剂，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未完全明确。我们观察到，细胞脱离增强了TRAIL对两种TRAIL耐药卵巢癌细胞系诱导的凋亡作用。这一过程伴随着半胱天冬酶激活增加，而半胱天冬酶8抑制剂IETD可阻断这一增加。细胞脱离抑制了Akt磷酸化。LY294002抑制磷脂酰肌醇3激酶也增强了TRAIL诱导的凋亡。LY294002在脱离细胞中进一步降低Akt活性，这转化为TRAIL处理后细胞死亡增加。我们的数据表明，细胞脱离通过降低TRAIL耐药卵巢癌细胞中的Akt活性增强了TRAIL诱导的杀伤作用，并提示抑制Akt可使TRAIL耐药细胞对TRAIL诱导的凋亡敏感。
