Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma.
Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma.
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DOI：
10.1038/cddis.2014.566
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发表时间：
2015-01-15
影响因子：
9
通讯作者：
Soroceanu L
中科院分区：
文献类型：
--
作者：
Singer E;Judkins J;Salomonis N;Matlaf L;Soteropoulos P;McAllister S;Soroceanu L
胶质母细胞瘤（GBM）对治疗的耐药性是肿瘤复发的最常见原因，90%的患者在首次诊断后5年内最终死亡。具有干细胞样特性的肿瘤细胞亚群，胶质瘤干细胞（GSC），特异性地被赋予抵抗或适应标准疗法，导致治疗抗性。几种抗癌剂，统称为氧化还原治疗剂，通过增加细胞内活性氧（ROS）水平发挥作用。在这项研究中，我们研究了GSC对大麻二酚（CBD）的反应和抗性的机制，CBD是一种无毒，非精神活性大麻素和氧化还原调节剂。使用原代GSC，我们表明CBD诱导ROS的强烈增加，这导致细胞存活、磷酸化（p）-AKT、自我更新的抑制和携带GSC的小鼠存活的显著增加。自我更新的抑制是由p-p38通路的激活和关键干细胞调节因子Sox 2、Id 1和p-STAT 3的下调介导的。CBD治疗后，GSC的一个子集成功适应，导致肿瘤再生长。微阵列、Taqman和功能测定揭示，治疗抗性由抗氧化反应系统Xc催化亚基xCT（SLC 7A 11（溶质载体家族7（阴离子氨基酸转运蛋白轻链），成员11））的增强表达和间充质（MES）标志物的ROS依赖性上调以及伴随的前神经（PN）标志物的下调（也称为PN-MES转变）介导。GSC的这种“重编程”发生在培养物和体内，并且部分是由于NFE 2L 2（NRF 2（核因子，红细胞2样））转录网络的激活。使用SLC 7A 11的遗传敲低和药理学抑制剂，我们证明了CBD治疗与系统Xc的抑制相结合导致协同ROS增加，从而产生强大的抗肿瘤作用，即降低GSC存活、自我更新和侵袭。我们的研究提供了新的机制的见解，氧化还原疗法的抗肿瘤活性，并表明，使用ROS的小分子调节剂的组合方法提供GBM的治疗效益。
Glioblastoma (GBM) resistance to therapy is the most common cause of tumor recurrence, which is ultimately fatal in 90% of the patients 5 years after initial diagnosis. A sub-population of tumor cells with stem-like properties, glioma stem cells (GSCs), is specifically endowed to resist or adapt to the standard therapies, leading to therapeutic resistance. Several anticancer agents, collectively termed redox therapeutics, act by increasing intracellular levels of reactive oxygen species (ROS). In this study, we investigated mechanisms underlying GSC response and resistance to cannabidiol (CBD), a non-toxic, non-psychoactive cannabinoid and redox modulator. Using primary GSCs, we showed that CBD induced a robust increase in ROS, which led to the inhibition of cell survival, phosphorylated (p)-AKT, self-renewal and a significant increase in the survival of GSC-bearing mice. Inhibition of self-renewal was mediated by the activation of the p-p38 pathway and downregulation of key stem cell regulators Sox2, Id1 and p-STAT3. Following CBD treatment, a subset of GSC successfully adapted, leading to tumor regrowth. Microarray, Taqman and functional assays revealed that therapeutic resistance was mediated by enhanced expression of the antioxidant response system Xc catalytic subunit xCT (SLC7A11 (solute carrier family 7 (anionic amino-acid transporter light chain), member 11)) and ROS-dependent upregulation of mesenchymal (MES) markers with concomitant downregulation of proneural (PN) markers, also known as PN–MES transition. This ‘reprogramming' of GSCs occurred in culture and in vivo and was partially due to activation of the NFE2L2 (NRF2 (nuclear factor, erythroid 2-like)) transcriptional network. Using genetic knockdown and pharmacological inhibitors of SLC7A11, we demonstrated that combining CBD treatment with the inhibition of system Xc resulted in synergistic ROS increase leading to robust antitumor effects, that is, decreased GSC survival, self-renewal, and invasion. Our investigation provides novel mechanistic insights into the antitumor activity of redox therapeutics and suggests that combinatorial approaches using small molecule modulators of ROS offer therapeutic benefits in GBM.