Williams Kaye J, Telfer Brian A, Airley Rachel E, Peters Hans P W, Sheridan Mary R, van der Kogel Albert J, Harris Adrian L, Stratford Ian J
School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Manchester, M13 9PL, UK.
Oncogene. 2002 Jan 10;21(2):282-90. doi: 10.1038/sj.onc.1205047.
We have investigated the role of HIF-1 in the cellular response to redox modulation via the inhibition of oxidative phosphorylation. We demonstrate that manipulation of redox in air, achieved by inhibiting cytochrome oxidase with cyanide, induces HIF-1 mediated transcription in wild-type CHO and HT1080 human tumour cells but not in CHO cells deficient in the oxygen responsive, HIF-1alpha sub-unit of HIF-1. Hypoglycaemia attenuates cyanide-mediated transcription in non-transformed HIF-1 wild-type CHO cells but not the human tumour derived cell line. Cells lacking either HIF-1alpha, or the second composite sub-unit of HIF-1, HIF-1beta, were markedly more sensitive to the combined stress of perturbed redox and hypoglycaemia than wild-type cells. As such conditions together with hypoxia are prevalent in tumours, these data suggest that HIF-1 may have a protective role in adaptation to the tumour micro-environment. In support of this we demonstrate that HIF-1alpha deficient cells are less tumorigenic than wild-type cells. They showed a reduced growth rate when grown as xenografts in nude mice. This was not related to vascular parameters that were identical to those found in HIF-1 wild-type tumours. The HIF-1 deficient tumours lacked focal expression of Glut-1 in hypoxic tumour regions. Compromised glucose uptake and metabolic adaptation to the tumour micro-environment may form the basis of the reduced tumorigenicity associated with these cells.
我们通过抑制氧化磷酸化研究了缺氧诱导因子-1（HIF-1）在细胞对氧化还原调节反应中的作用。我们证明，在空气中通过用氰化物抑制细胞色素氧化酶来操纵氧化还原，可诱导野生型中国仓鼠卵巢（CHO）细胞和人HT1080肿瘤细胞中HIF-1介导的转录，但在缺乏对氧有反应的HIF-1α亚基（HIF-1的一个亚基）的CHO细胞中则不会。低血糖可减弱非转化的HIF-1野生型CHO细胞中氰化物介导的转录，但对人肿瘤衍生细胞系则无此作用。缺乏HIF-1α或HIF-1的第二个复合亚基HIF-1β的细胞，对氧化还原紊乱和低血糖联合应激的敏感性明显高于野生型细胞。由于这些情况与缺氧一起在肿瘤中普遍存在，这些数据表明HIF-1可能在适应肿瘤微环境中具有保护作用。为此，我们证明HIF-1α缺陷细胞的致瘤性低于野生型细胞。当作为异种移植物在裸鼠中生长时，它们的生长速度降低。这与血管参数无关，这些参数与在HIF-1野生型肿瘤中发现的参数相同。HIF-1缺陷肿瘤在缺氧肿瘤区域缺乏葡萄糖转运蛋白1（Glut-1）的局灶性表达。葡萄糖摄取受损和对肿瘤微环境的代谢适应可能是这些细胞致瘤性降低的基础。
