Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors.
Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors.
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DOI：
10.3892/ijo.30.5.1163
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发表时间：
2007-05
影响因子：
5.2
通讯作者：
Makiko Uchida;M. Iwase;Sayaka Takaoka;Sayaka Yoshiba;Gen Kondo;Hitoshi Watanabe;M. Ohashi;M. Nagumo;S. Shintani
中科院分区：
文献类型：
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作者：
Makiko Uchida;M. Iwase;Sayaka Takaoka;Sayaka Yoshiba;Gen Kondo;Hitoshi Watanabe;M. Ohashi;M. Nagumo;S. Shintani
一般来说，口腔鳞状细胞癌（OSCC）细胞在体外培养过程中对肿瘤坏死因子相关凋亡诱导配体（TRAIL）介导的凋亡具有相对抵抗力。在此，我们研究了磷脂酰肌醇3-激酶（PI 3-K）/Akt在这些细胞的存活和凋亡中的作用。PI 3-K抑制剂wortmannin和LY 294002显著抑制Akt磷酸化，促进TRAIL介导的OSCC细胞凋亡。向PI 3-K通道处理的细胞中添加TRAIL导致caspase-8活化和线粒体膜电位的损失。此外，caspase-3，-8和-9的抑制剂降低PI 3-K抑制剂对TRAIL介导的凋亡的加速作用。这些结果表明PI 3-K抑制剂对TRAIL介导的凋亡的促凋亡作用可能有助于外在和内在途径。尽管PI 3-K抑制剂不影响TRAIL受体DR 4和DR 5的表达，但我们观察到细胞FLICE抑制蛋白（c-FLIP）、Bcl-2、细胞凋亡抑制蛋白-1（cIAP-1）和X连锁IAP（XIAP）的表达显著降低，而Bax上调，并且在Bcl-xL、巴克或cIAP-2的表达中未观察到显著差异。因此，PI 3-K/Akt信号通路通过调节c-FLIP、Bcl-2、Bax、cIAP-1和XIAP的表达来部分调节TRAIL介导的OSCC细胞凋亡。这些结果表明，PI 3-K抑制剂可能代表了一种新的策略，克服阻力TRAIL介导的凋亡在口腔鳞癌细胞。
In general, oral squamous cell carcinoma (OSCC) cells are relatively resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis during culture in vitro. Here, we studied the role of phosphatidylinositol 3-kinase (PI 3-K)/Akt in survival and apoptosis of these cells. The PI 3-K inhibitors wortmannin and LY294002 markedly suppressed phosphorylation of Akt and accelerated TRAIL-mediated apoptosis in OSCC cells. Addition of TRAIL to PI 3-K inhibitor-treated cells resulted in caspase-8 activation and loss of mitochondrial membrane potential. Furthermore, inhibitors of caspase-3, -8 and -9 reduced the accelerative effect of PI 3-K inhibitors on TRAIL-mediated apoptosis. These results suggest that the pro-apoptotic effect of PI 3-K inhibitors on TRAIL-mediated apoptosis may contribute to both the extrinsic and intrinsic pathways. Although PI 3-K inhibitors did not affect expression of the TRAIL receptors DR4 and DR5, we observed a marked reduction in expression of cellular FLICE-inhibitory protein (c-FLIP), Bcl-2, cellular inhibitor of apoptosis protein-1 (cIAP-1) and X-linked IAP (XIAP), whereas Bax was up-regulated and no significant difference was observed in expression of Bcl-xL, Bak or cIAP-2. Therefore, the PI 3-K/Akt signaling pathway provides partial regulation of TRAIL-mediated apoptosis in OSCC cells via modulation of c-FLIP, Bcl-2, Bax, cIAP-1 and XIAP expression. These results suggest that PI 3-K inhibitors may represent a novel strategy for overcoming resistance to TRAIL-mediated apoptosis in OSCC cells.