Abstract
We asked whether inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is highly active in cancer stem cells (CSCs) and upregulated in response to genotoxic treatments, promote γ-irradiationγIR)-induced cell death in highly radioresistant, patient-derived stem-like glioma cells (SLGCs). Surprisingly, in most cases the inhibitors did not promote γIR-induced cell death. In contrast, the strongly cytostatic Ly294002 and PI-103 even tended to reduce it. Since autophagy was induced we examined whether addition of the clinically applicable autophagy inhibitor chloroquine (CQ) would trigger cell death in SLGCs. Triple therapy with CQ at doses as low as 5 to 10 µM indeed caused strong apoptosis. At slightly higher doses, CQ alone strongly promoted γIR-induced apoptosis in all SLGC lines examined. The strong apoptosis in combinations with CQ was invariably associated with strong accumulation of the autophagosomal marker LC3-II, indicating inhibition of late autophagy. Thus, autophagy-promoting effects of PI3K/Akt pathway inhibitors apparently hinder cell death induction in γ-irradiated SLGCs. However, as we show here for the first time, the late autophagy inhibitor CQ strongly promotes γIR-induced cell death in highly radioresistant CSCs, and triple combinations of CQ, γIR and a PI3K/Akt pathway inhibitor permit reduction of the CQ dose required to trigger cell death.
Highlights
Glioblastoma multiforme (GBM) WHO grade IV is the most common and the most aggressive brain tumor
Since autophagy is usually upregulated as a survival mechanism in response to PI3K/Akt pathway inhibitors and in many cell types in response to cIR [9,24,25,26,27], we examined whether autophagy is induced in stem-like glioma cells (SLGCs) treated with cIR and/or the three different PI3K/Akt pathway inhibitors
It is generally assumed that cancer stem cells (CSCs) crucially contribute to the resistance of malignant tumors to chemo- and radiotherapy and that the Akt pathway is important for CSC survival
Summary
Glioblastoma multiforme (GBM) WHO grade IV is the most common and the most aggressive brain tumor. It is uniformly fatal, and standard treatment with surgical resection plus temozolomidebased radiochemotherapy gives a median survival of only 14.6 months [1]. PI3K/Akt signaling stimulates a large variety of downstream molecules, some through the mammalian target of rapamycin (mTOR). Both autophagy, a lysosome-dependent degradation and recycling pathway triggered primarily as a survival response to various sublethal stresses, and apoptosis, the most common form of programmed cell death, are regulated by PI3K/Akt/mTOR signaling [7,8,9]. The PI3K/Akt pathway is regarded as a stemness pathway important for survival of cancer stem cells (CSCs) [10]
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