Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
FEBS J. 2009 Dec;276(24):7291-304. doi: 10.1111/j.1742-4658.2009.07441.x.
Aberrant differentiation is a characteristic feature of neoplastic transformation, while hypoxia in solid tumors is believed to be linked to aggressive behavior and poor prognosis. However, the possible relationship between hypoxia and differentiation in malignancies remains poorly defined. Here we show that rat C6 and primary human malignant glioma cells can be induced to differentiate into astrocytes by the well-known adenylate cyclase activator forskolin. However, hypoxia-inducible factor-1alpha expression stimulated by the hypoxia mimetics cobalt chloride or deferoxamine blocks this differentiation and this effectiveness is reversible upon withdrawal of the hypoxia mimetics. Importantly, knockdown of hypoxia inducible factor-1alpha by RNA interference restores the differentiation capabilities of the cells, even in the presence of cobalt chloride, whereas stabilization of hypoxia-inducible factor-1alpha through retarded ubiquitination by von Hippel-Lindau tumor suppressor gene silence abrogates the induced differentiation. Moreover, targeting of HIF-1 using chetomin, a disrupter of HIF-1 binding to its transcriptional co-activator CREB-binding protein (CBP)/p300, abolishes the differentiation-inhibitory effect of hypoxia-inducible factor-1alpha. Administration of chetomin in combination with forskolin significantly suppresses malignant glioma growth in an in vivo xenograft model. Analysis of 95 human glioma tissues revealed an increase of hypoxia-inducible factor-1alpha protein expression with progressing tumor grade. Taken together, these findings suggest a key signal transduction pathway involving hypoxia-inducible factor-1alpha that contributes to a differentiation defect in malignant gliomas and sheds new light on the differentiation therapy of solid tumors by targeting hypoxia-inducible factor-1alpha.
异常分化是肿瘤转化的一个特征，而实体瘤中的缺氧被认为与侵袭性行为和不良预后有关。然而，缺氧与恶性肿瘤分化之间的可能关系仍未得到明确界定。在这里，我们显示大鼠 C6 和原代人恶性神经胶质瘤细胞可以通过众所周知的腺苷酸环化酶激活剂 forskolin诱导分化为星形胶质细胞。然而，缺氧诱导因子-1α的表达由缺氧模拟物氯化钴或去铁胺刺激，阻断这种分化，并且这种有效性在缺氧模拟物撤回后是可逆的。重要的是，通过 RNA 干扰敲低缺氧诱导因子-1α可恢复细胞的分化能力，即使在存在氯化钴的情况下也是如此，而通过 von Hippel-Lindau 肿瘤抑制基因沉默来延迟泛素化稳定缺氧诱导因子-1α则会破坏诱导的分化。此外，通过 chetomin 靶向 HIF-1，chetomin 是一种破坏 HIF-1 与其转录共激活因子 CREB 结合蛋白 (CBP)/p300 结合的抑制剂，可消除缺氧诱导因子-1α的分化抑制作用。chetomin 与 forskolin 联合给药可显著抑制体内异种移植模型中的恶性神经胶质瘤生长。对 95 例人胶质瘤组织的分析显示，缺氧诱导因子-1α蛋白表达随着肿瘤分级的进展而增加。总之，这些发现表明涉及缺氧诱导因子-1α的关键信号转导途径导致恶性神经胶质瘤分化缺陷，并为通过靶向缺氧诱导因子-1α进行实体瘤分化治疗提供了新的思路。
