Targeting cancer stem cells in glioblastoma multiforme using mTOR inhibitors and the differentiating agent all-trans retinoic acid
Targeting cancer stem cells in glioblastoma multiforme using mTOR inhibitors and the differentiating agent all-trans retinoic acid
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DOI：
10.3892/or.2013.2625
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发表时间：
2013-10-01
期刊：
影响因子：
4.2
通讯作者：
Jhanwar-Uniyal, Meena
中科院分区：
文献类型：
--
作者：
Friedman, Marissa D.;Jeevan, Dhruve S.;Jhanwar-Uniyal, Meena
多形性胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤，尽管目前的治疗方式，预后仍很差。肿瘤生长的复发归因于治疗抵抗性癌症干细胞（CSCs）的存在。因此，靶向这些CSCs对于治疗这种疾病至关重要。rapamycin的Mechanistic target of rapamycin （mTOR）形成mTORC1和mTORC2两个多蛋白复合物，分别调控增殖和迁移。mTOR的异常功能已被证明存在于GBM CSCs中。全反式维甲酸（ATRA）是视黄醇的衍生物，可引起csc和正常神经祖细胞的分化。本研究的目的是描述mTOR在CSC维持中的作用，并建立使用分化剂和mTOR通路抑制剂靶向GBM CSC的机制。结果表明，ATRA导致了CSCs的分化，正如干细胞标记物Nestin的缺失所证明的那样。这些观察结果被western blotting证实，在ATRA治疗后，Nestin的表达呈时间依赖性下降。尽管与mTOR（雷帕霉素）、PI3K （LY294002）和MEK1/2 （U0126）抑制剂联合使用，这种效果仍然存在。在ATRA治疗后，活化的细胞外信号调节激酶1/2 （pERK1/2）的表达增强，不依赖于mTOR通路抑制剂。经神经球直径测定，ATRA单独或联合雷帕霉素治疗后，CSCs的增殖降低。ATRA、雷帕霉素和LY29002单独治疗可降低GBM细胞的运动能力。然而，联合治疗增强了对迁移的抑制作用，提示协同作用。这些发现表明，atraini诱导的分化是通过ERK1/2通路介导的，并强调了在治疗GBM时使用分化剂和mTOR通路抑制剂的重要性。
Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, portends a poor prognosis despite current treatment modalities. Recurrence of tumor growth is attributed to the presence of treatment-resistant cancer stem cells (CSCs). The targeting of these CSCs is therefore essential in the treatment of this disease. Mechanistic target of rapamycin (mTOR) forms two multiprotein complexes, mTORC1 and mTORC2, which regulate proliferation and migration, respectively. Aberrant function of mTOR has been shown to be present in GBM CSCs. All-trans retinoic acid (ATRA), a derivative of retinol, causes differentiation of CSCs as well as normal neural progenitor cells. The purpose of this investigation was to delineate the role of mTOR in CSC maintenance, and to establish the mechanism of targeting GBM CSCs using differentiating agents along with inhibitors of the mTOR pathways. The results demonstrated that ATRA caused differentiation of CSCs, as demonstrated by the loss of the stem cell marker Nestin. These observations were confirmed by western blotting, which demonstrated a time-dependent decrease in Nestin expression following ATRA treatment. This effect occurred despite combination with mTOR (rapamycin), PI3K (LY294002) and MEK1/2 (U0126) inhibitors. Expression of activated extracellular signal-regulated kinase 1/2 (pERK1/2) was enhanced following treatment with ATRA, independent of mTOR pathway inhibitors. Proliferation of CSCs, determined by neurosphere diameter, was decreased following treatment with ATRA alone and in combination with rapamycin. The motility of GBM cells was mitigated by treatment with ATRA, rapamycin and LY29002 alone. However, combination treatment augmented the inhibitory effect on migration suggesting synergism. These findings indicate that ATRAinduced differentiation is mediated via the ERK1/2 pathway, and underscores the significance of including differentiating agents along with inhibitors of mTOR pathways in the treatment of GBM.