The mechanism of escape from hypoxia-induced apoptosis in squamous cell carcinoma cells.

转录因子缺氧诱导因子1（hypoxia-inducible factor 1, HIF-1）在实体瘤细胞的生长和存活中起着重要作用。HIF-1α的过度表达已经在许多人类肿瘤中得到证实，并预示着对放化疗的不良反应。我们研究了HIF-1α诱导的人口腔鳞状细胞癌细胞（OSCC）存活途径以及HIF-1α对化疗药物和γ射线敏感性的影响。结果表明，强迫表达HIF-1α通过抑制线粒体中细胞色素c的释放来抑制缺氧诱导的OSCC细胞凋亡。过表达HIF-1α抑制活性氧（ROS）的产生，细胞内Ca^<2+>浓度升高，线粒体膜电位降低，细胞色素c在胞质内积累，导致caspase-9和caspase-3失活。抗凋亡细胞Bcl-2和Bcl-X_L水平升高，促凋亡细胞Bax和Bak水平降低，在过表达hif -1α-的OSCC细胞系中表现明显。HIF-1α的过表达也增加了Akt和细胞外信号调节激酶（ERK）的磷酸化水平。这些发现表明HIF-1α通过抑制细胞色素c释放和激活Akt和ERK两种机制阻止凋亡细胞死亡。化疗药物和γ射线治疗增强了HIF-1α的表达和核易位，OSCC细胞对药物和γ射线的敏感性与HIF-1α蛋白的表达水平呈负相关。过表达HIF-1α可诱导OSCC细胞对抗癌药物产生更强的抗性，小干扰RNA下调HIF-1α的表达可增强OSCC细胞对抗癌药物的敏感性。在hif -1α-敲低的OSCC细胞中，p -糖蛋白、血红素加氧酶-1、锰超氧化物歧化酶和铜蓝蛋白的表达下调，抗癌药物治疗后细胞内化疗药物和活性氧水平维持在较高水平。这些结果表明，下调HIF-1α表达是一种有效的癌症治疗策略。少

The transcription factor hypoxia-inducible factor 1(HIF-1) plays an important role in solid tumor cell growth and survival. Over-expression of HIF-1α has been demonstrated in many human tumors and predicts a poor response to chemoradiotherapy. We examined the HIF-1α-induced survival pathways and the influence of HIF-1α on the susceptibility to chemotherapeutic drugs and γ-rays in human oral squamous cell carcinoma cell (OSCC) lines. The results showed that forced expression of HIF-1α suppressed hypoxia-induced apoptosis of OSCC lines by inhibiting cytochrome c release from mitochondria. Over-expression of HIF-1α inhibited the generation of reactive oxygen species (ROS), elevation of intracellular Ca^<2+> concentration, reduction of mitochondrial membrane potential, and cytosolic accumulation of cytochrome c, which resulted in the inactivation of caspase-9 and caspase-3. In addition, anti-apoptotic Bcl-2 and Bcl-X_L levels were increased and pro-apoptotic Bax and Bak levels were decreas … More ed in the HIF-1α-overexpressing OSCC line. Over-expression of HIF-1α also increased the levels of phosphorylation of Akt and extracellular signal-regulated kinases (ERK). These findings indicate that HIF-1α prevents apoptotic cell death through two mechanisms including inhibition of cytochrome c release and activation of Akt and ERK. Treatment with chemotherapeutic drugs and γ-rays enhanced the expression and nuclear translocation of HIF-1α and the susceptibility of OSCC cells to the drugs and γ-rays was negatively correlated with the expression level of HIF-1α protein. The over-expression of HIF-1α induced OSCC cells more resistant to the anticancer agents and the down-regulation of HIF-1α expression by small interfering RNA enhanced the susceptibility of OSCC cells to them. In the HIF-1α-knockdown OSCC cells, the expression of P-glycoprotein, heme oxygenase-1, manganese-superoxide dismutase and ceruloplasmin were down-regulated and the intracellular levels of chemotherapeutic drugs and reactive oxygen species were sustained at higher levels after the treatment with the anticancer agents. These results suggest that down-regulation of HIF-1α expression is an effective strategy for cancer treatment. Less