Carnosol controls the human glioblastoma stemness features through the epithelial-mesenchymal transition modulation and the induction of cancer stem cell apoptosis.
Carnosol controls the human glioblastoma stemness features through the epithelial-mesenchymal transition modulation and the induction of cancer stem cell apoptosis.
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DOI：
10.1038/s41598-017-15360-2
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发表时间：
2017-11-09
影响因子：
4.6
通讯作者：
Martini C
中科院分区：
文献类型：
--
作者：
Giacomelli C;Daniele S;Natali L;Iofrida C;Flamini G;Braca A;Trincavelli ML;Martini C
胶质母细胞瘤（GBM）的主要特征是细胞增殖率高、侵袭性强和对化疗耐药。GBM侵袭性与呈现干细胞样特性的少数细胞群体（癌症干细胞样细胞，CSC）和肿瘤细胞获得间充质表型（上皮-间充质转化，EMT）的能力广泛相关。鼠尾草酚（Carnosol，CAR）是MDM 2/p53复合物的天然抑制剂，对多种肿瘤（包括GBM）的抑制作用已引起人们的关注。在本文中，评估了CAR对U87 MG衍生的CSC活力和干性特征的影响。CAR通过p53功能再激活降低CSC形成率并促进CSC凋亡细胞死亡。此外，CAR能够控制TNF-α/TGF-β诱导的EMT，抵消细胞因子对EMT主调节基因（Slug，Snail，Twist和ZEB 1）的影响，并调节miR-200 c的激活，miR-200 c是EMT过程中的关键参与者。最后，CAR能够增加替莫唑胺（TMZ）的抗增殖作用。这些发现表明CAR影响调节GBM干性的复杂机制的不同细胞内机制。第一次，二萜被强调为开发能够减少干特性的药剂的有希望的先导，从而控制GBM的侵略性。
A high cell proliferation rate, invasiveness and resistance to chemotherapy are the main features of glioblastoma (GBM). GBM aggressiveness has been widely associated both with a minor population of cells presenting stem-like properties (cancer stem-like cells, CSCs) and with the ability of tumor cells to acquire a mesenchymal phenotype (epithelial-mesenchymal transition, EMT). Carnosol (CAR), a natural inhibitor of MDM2/p53 complex, has been attracted attention for its anti-cancer effects on several tumor types, including GBM. Herein, the effects of CAR on U87MG-derived CSC viability and stemness features were evaluated. CAR decreased the rate of CSC formation and promoted the CSC apoptotic cell death through p53 functional reactivation. Moreover, CAR was able to control the TNF-α/TGF-β-induced EMT, counteracting the effects of the cytokine on EMT master regulator genes (Slug, Snail, Twist and ZEB1) and modulating the activation of miR-200c, a key player in the EMT process. Finally, CAR was able to increase the temozolomide (TMZ) anti-proliferative effects. These findings demonstrate that CAR affected the different intracellular mechanism of the complex machinery that regulates GBM stemness. For the first time, the diterpene was highlighted as a promising lead for the development of agents able to decrease the stemness features, thus controlling GBM aggressiveness.
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