Griguer Corinne E, Oliva Claudia R, Gobin Eric, Marcorelles Pascale, Benos Dale J, Lancaster Jack R, Gillespie G Yancey
Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
PLoS One. 2008;3(11):e3655. doi: 10.1371/journal.pone.0003655. Epub 2008 Nov 5.
Mitochondria dysfunction and hypoxic microenvironment are hallmarks of cancer cell biology. Recently, many studies have focused on isolation of brain cancer stem cells using CD133 expression. In this study, we investigated whether CD133 expression is regulated by bioenergetic stresses affecting mitochondrial functions in human glioma cells. First, we determined that hypoxia induced a reversible up-regulation of CD133 expression. Second, mitochondrial dysfunction through pharmacological inhibition of the Electron Transport Chain (ETC) produced an up-regulation of CD133 expression that was inversely correlated with changes in mitochondrial membrane potential. Third, generation of stable glioma cells depleted of mitochondrial DNA showed significant and stable increases in CD133 expression. These glioma cells, termed rho(0) or rho(0), are characterized by an exaggerated, uncoupled glycolytic phenotype and by constitutive and stable up-regulation of CD133 through many cell passages. Moreover, these rho(0) cells display the ability to form "tumor spheroids" in serumless medium and are positive for CD133 and the neural progenitor cell marker, nestin. Under differentiating conditions, rho(0) cells expressed multi-lineage properties. Reversibility of CD133 expression was demonstrated by transfering parental mitochondria to rho(0) cells resulting in stable trans-mitochondrial "cybrid" clones. This study provides a novel mechanistic insight about the regulation of CD133 by environmental conditions (hypoxia) and mitochondrial dysfunction (genetic and chemical). Considering these new findings, the concept that CD133 is a marker of brain tumor stem cells may need to be revised.
线粒体功能障碍和缺氧微环境是癌细胞生物学的标志。最近，许多研究集中于利用CD133表达来分离脑癌干细胞。在本研究中，我们调查了在人胶质瘤细胞中，CD133表达是否受影响线粒体功能的生物能量应激调控。首先，我们确定缺氧诱导了CD133表达的可逆上调。其次，通过对电子传递链（ETC）进行药理学抑制导致的线粒体功能障碍使CD133表达上调，且该上调与线粒体膜电位的变化呈负相关。第三，线粒体DNA缺失的稳定胶质瘤细胞系显示CD133表达显著且稳定增加。这些胶质瘤细胞，称为rho(0)细胞，其特征是具有夸张的、解偶联的糖酵解表型，并且在多次细胞传代过程中CD133呈组成性和稳定上调。此外，这些rho(0)细胞在无血清培养基中具有形成“肿瘤球”的能力，并且CD133和神经祖细胞标志物巢蛋白呈阳性。在分化条件下，rho(0)细胞表现出多谱系特性。将亲代线粒体转移至rho(0)细胞产生稳定的转线粒体“胞质杂种”克隆，证明了CD133表达的可逆性。本研究提供了关于环境条件（缺氧）和线粒体功能障碍（遗传和化学）对CD133调控的新机制见解。考虑到这些新发现，CD133是脑肿瘤干细胞标志物这一概念可能需要修正。
