Department of Neurosurgery, Mackay Memorial Hospital, Taipei 104, Taiwan.
Biomed Pharmacother. 2012 Sep;66(6):433-8. doi: 10.1016/j.biopha.2012.03.003. Epub 2012 Mar 27.
Human WWOX gene encoding WW domain-containing oxidoreductase, named WWOX, FOR, or WOX1, has been studied in various types of cancer cells and shown to be a tumor suppressor with pro-apoptotic properties. Mutation or gain-of-function of p53 in glioma cells is associated with resistance to radiation therapy and poor prognosis. In this study, we overexpressed WOX1 to examine the pro-apoptotic activity against human glioblastoma cells harboring mutant p53.
Overexpression of WOX1 in glioblastoma cell lines and apoptosis-related assays were performed.
Our results showed that overexpressed WOX1 induced apoptosis of glioblastoma U373MG harboring mutant p53 by causing hypoploidy and DNA fragmentation. However, ectopic WOX1 had no effect with U87MG possessing wild type p53. Unlike temozolomide, WOX1 induced apoptosis of U373MG cells via a mitochondria-independent and caspase-3-independent pathway.
Overexpression of WOX1 preferentially inhibited viability and induced apoptosis in human glioblastoma cells expressing mutant p53 via a mechanism independent of the intrinsic apoptotic pathway. Conceivably, the survival of human glioblastoma cells depends upon interactions between the gain-of-function of p53 and WOX1. This suggests that modulation of WOX1 expression may be a novel strategy for treating human glioblastoma cells with mutant p53.
人类 WW 结构域包含氧化还原酶基因 WWOX 编码 WW 结构域，命名为 WWOX、FOR 或 WOX1，已在各种类型的癌细胞中进行了研究，被证明是具有促凋亡特性的肿瘤抑制因子。胶质母细胞瘤细胞中 p53 的突变或功能获得与对放射治疗的抵抗和预后不良有关。在这项研究中，我们过表达 WOX1 以检查对携带突变 p53 的人胶质母细胞瘤细胞的促凋亡活性。
在胶质母细胞瘤细胞系中过表达 WOX1 并进行凋亡相关测定。
我们的结果表明，过表达的 WOX1 通过引起亚二倍体和 DNA 片段化诱导携带突变 p53 的胶质母细胞瘤 U373MG 细胞凋亡。然而，外源性 WOX1 对具有野生型 p53 的 U87MG 没有影响。与替莫唑胺不同，WOX1 通过线粒体非依赖性和 caspase-3 非依赖性途径诱导 U373MG 细胞凋亡。
过表达 WOX1 通过独立于内在凋亡途径的机制优先抑制表达突变 p53 的人胶质母细胞瘤细胞的活力并诱导其凋亡。可以想象，人胶质母细胞瘤细胞的存活取决于 p53 的功能获得与 WOX1 之间的相互作用。这表明调节 WOX1 表达可能是治疗具有突变 p53 的人胶质母细胞瘤细胞的新策略。
