Sensitization of glioma cells to tamoxifen-induced apoptosis by Pl3-kinase inhibitor through the GSK-3beta/beta-catenin signaling pathway.

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Li C, Zhou C, Wang S, Feng Y, Lin W, Lin S, Wang Y, Huang H, Liu P, Mu YG, Shen X

Sensitization of glioma cells to tamoxifen-induced apoptosis by Pl3-kinase inhibitor through the GSK-3beta/beta-catenin signaling pathway.

PLoS One. 2011;6(10):e27053. doi: 10.1371/journal.pone.0027053. Epub 2011 Oct 27.

PubMed ID

22046442 [ View in PubMed

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Abstract

Malignant gliomas represent one of the most aggressive types of cancers and their recurrence is closely linked to acquired therapeutic resistance. A combination of chemotherapy is considered a promising therapeutic model in overcoming therapeutic resistance and enhancing treatment efficacy. Herein, we show by colony formation, Hochest 33342 and TUNEL staining, as well as by flow cytometric analysis, that LY294002, a specific phosphatidylinositide-3-kinase (PI3K) inhibitor, enhanced significantly the sensitization of a traditional cytotoxic chemotherapeutic agent, tamoxifen-induced apoptosis in C6 glioma cells. Activation of PI3K signaling pathway by IGF-1 protected U251 cells from apoptosis induced by combination treatment of LY294002 and tamoxifen. Interference of PI3K signaling pathway by PI3K subunit P85 siRNA enhanced the sensitization of U251 glioma cells to tamoxifen -induced apoptosis. By Western blotting, we found that combination treatment showed lower levels of phosphorylated Akt(Ser473) and GSK-3beta(Ser9) than a single treatment of LY294002. Further, we showed a significant decrease of nuclear beta-catenin by combination treatment. In response to the inhibition of beta-catenin signaling, mRNA and protein levels of Survivin and the other three antiapoptotic genes Bcl-2, Bcl-xL, and Mcl-1 were significantly decreased by combination treatment. Our results indicated that the synergistic cytotoxic effect of LY294002 and tamoxifen is achieved by the inhibition of GSK-3beta/beta-catenin signaling pathway.

DrugBank Data that Cites this Article

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
LY-294002	Experimental	BCL2	596	upregulated	2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one results in increased expression of BCL2 mRNA	18q21.33
LY-294002	Experimental	BIRC5	332	upregulated	2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one results in increased expression of BIRC5 mRNA	17q25.3