Abstract
Temozolomide (TMZ) is a promising chemotherapeutic agent for treating glioblastomas. However, resistance develops quickly with a high frequency. Glioblastoma stem cells (GSCs) causing resistance to drug therapy were considered to be one of the key factors. The mechanisms underlying GSCs resistance to TMZ are not fully understood. MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance. Our previous studies showed that miR-125b was necessary for GSCs fission, and inhibition of which could enhance the chemosensitivity of GSCs to TMZ. Recent studies have evidence that a variety of drugs and upstream factors work through PI3K/Akt pathway, and the effects of PI3K/Akt pathway inhibition on GSCs were much more than non-GSCs. In this study, we found that PI3K inhibitor combined with miR-125b inhibitor caused a marked increase of TMZ-induced GSC proliferation and invasiveness inhibition. To explore the potential mechanism, we found that this novel combinatorial regimen leads to changes of inactivation of Wnt/β-catenin pathway which regulates a series of cell activities including cell apoptosis, proliferation, differentiation, and metabolism. Taken together, our data strongly support an important role for PI3K inhibitor and miR-125b inhibitor on conferring GSCs resistance to TMZ through targeting Wnt/β-catenin signaling pathway.
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Acknowledgments
This work was supported by the China Natural Science Foundation (81000963 and 81370062), Jiangsu Province's 333 Talent Program (BRA2011046), Jiangsu Province "six personnel peak" funded projects (2013-WSN-028), the Natural Science Foundation of Suzhou (no. SYS201307), Jiangsu Province's Natural Science Foundation (BK2012670), Medical Research Foundation by Jiangsu Province Health Department (YG201301 and Z201318), the Clinical Technology Development of Jiangsu University (JLY20120053), Suzhou City Xing Wei Youth Science and technology project (kjxw2014059), the Kunshan Social Development Foundation (KS1006, KS1009), and the Suzhou Social Development Foundation (SYS201063). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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All authors have declared the sources of research funding for this manuscript and have no financial or other contractual agreements that might cause (or be perceived as causes of) conflicts of interest.
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Editor: Tetsuji Okamoto
Lei Shi, Xifeng Fei and Zhimin Wang contributed equally to this work.
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Shi, L., Fei, X., Wang, Z. et al. PI3K inhibitor combined with miR-125b inhibitor sensitize TMZ-induced anti-glioma stem cancer effects through inactivation of Wnt/β-catenin signaling pathway. In Vitro Cell.Dev.Biol.-Animal 51, 1047–1055 (2015). https://doi.org/10.1007/s11626-015-9931-x
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DOI: https://doi.org/10.1007/s11626-015-9931-x