Secreted frizzled-related protein 4 inhibits glioma stem-like cells by reversing epithelial to mesenchymal transition, inducing apoptosis and decreasing cancer stem cell properties.
Secreted frizzled-related protein 4 inhibits glioma stem-like cells by reversing epithelial to mesenchymal transition, inducing apoptosis and decreasing cancer stem cell properties.
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DOI：
10.1371/journal.pone.0127517
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Warrier S
中科院分区：
文献类型：
--
作者：
Bhuvanalakshmi G;Arfuso F;Millward M;Dharmarajan A;Warrier S
Wnt信号通路参与调节肿瘤干细胞的自我更新、增殖和维持。我们探讨了Wnt拮抗剂分泌型卷曲相关蛋白4（sFRP 4）在调节人胶质母细胞瘤细胞系U87和U373的CSC中上皮向间质转化（EMT）的作用。通过逆转EMT，sFRP 4化学致敏的CSC富集细胞对最常用的抗胶质母细胞瘤药物替莫唑胺（TMZ）敏感。sFRP 4 +TMZ处理抑制细胞运动、集落形成和体外侵袭，这与标志物从间质（Twist、Snail、N-cadherin）表达到上皮（E-cadherin）表达的转换相关。sFRP 4处理引起Wnt-Ca 2+途径的激活，其拮抗Wnt/β-连环蛋白途径。值得注意的是，sFRP 4的化学增敏作用与耐药标志物ABCG 2、ABCC 2和ABCC 4的表达减少相关。使用裸鼠在体内证明了sFRP 4 +TMZ治疗的功效，其显示使用用sFRP 4 +TMZ预处理的CSC的最小肿瘤植入。这些研究表明，sFRP 4治疗将有助于通过Wnt/β-连环蛋白途径调节EMT来改善对神经胶质瘤中常用化疗药物的反应。这些发现可以用于设计更好的靶向策略，以改善化学反应并最终消除胶质母细胞瘤CSC。
The Wnt pathway is integrally involved in regulating self-renewal, proliferation, and maintenance of cancer stem cells (CSCs). We explored the effect of the Wnt antagonist, secreted frizzled-related protein 4 (sFRP4), in modulating epithelial to mesenchymal transition (EMT) in CSCs from human glioblastoma cells lines, U87 and U373. sFRP4 chemo-sensitized CSC-enriched cells to the most commonly used anti-glioblastoma drug, temozolomide (TMZ), by the reversal of EMT. Cell movement, colony formation, and invasion in vitro were suppressed by sFRP4+TMZ treatment, which correlated with the switch of expression of markers from mesenchymal (Twist, Snail, N-cadherin) to epithelial (E-cadherin). sFRP4 treatment elicited activation of the Wnt-Ca2 + pathway, which antagonizes the Wnt/ß-catenin pathway. Significantly, the chemo-sensitization effect of sFRP4 was correlated with the reduction in the expression of drug resistance markers ABCG2, ABCC2, and ABCC4. The efficacy of sFRP4+TMZ treatment was demonstrated in vivo using nude mice, which showed minimum tumor engraftment using CSCs pretreated with sFRP4+TMZ. These studies indicate that sFRP4 treatment would help to improve response to commonly used chemotherapeutics in gliomas by modulating EMT via the Wnt/ß-catenin pathway. These findings could be exploited for designing better targeted strategies to improve chemo-response and eventually eliminate glioblastoma CSCs.
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影响因子：
7.2
作者：
Drake, JM;Friis, RR;Dharmarajan, AM
通讯作者：
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影响因子：
4.8
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影响因子：
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通讯作者：
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