Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells

Abstract

Glioblastoma, the most intractable cerebral tumor, is highly lethal. Recent studies suggest that cancer stem-like cells (CSLCs) have the capacity to repopulate tumors and mediate radio- and chemoresistance, implying that future therapies may need to turn from the elimination of rapidly dividing, but differentiated, tumor cells to specifically targeting the minority of tumor cells that repopulate the tumor. However, the mechanism by which glioblastoma CSLCs maintain their immature stem-like state or, alternatively, become committed to differentiation is poorly understood. Here, we show that the inactivation of mammalian target of rapamycin (mTor) by the mTor inhibitor rapamycin or knockdown of mTor reduced sphere formation and the expression of neural stem cell (NSC)/progenitor markers in CSLCs of the A172 glioblastoma cell line. Interestingly, combination treatment with rapamycin and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, not only reduced the expression of NSC/progenitor markers more efficiently than single-agent treatment, but also increased the expression of βIII-tubulin, a neuronal differentiation marker. Consistent with these results, a dual PI3K/mTor inhibitor, NVP-BEZ235, elicited a prodifferentiation effect on A172 CSLCs. Moreover, A172 CSLCs, which were induced to undergo differentiation by pretreatment with NVP-BEZ235, exhibited a significant decrease in their tumorigenicity when transplanted either subcutaneously or intracranially. Importantly, similar results were obtained when patient-derived glioblastoma CSLCs were used. These findings suggest that the PI3K/mTor signaling pathway is critical for the maintenance of glioblastoma CSLC properties, and targeting both mTor and PI3K of CSLCs may be an effective therapeutic strategy in glioblastoma.

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

“…In our study, as evidenced by the nanomolar range of half maximal inhibitory concentration values, NVP-BEZ235 can effectively block GSC proliferation. NVP-BEZ235 also had a prodifferentiation effect on A172 cells, which is consistent with previously published research [21] . We adopted a combination strategy and observed that NVP-BEZ235 is also a potent radiosensitizer of GSCs; this is based on the results of two gold standard techniques used to determine cellular radiosensitivity (ie, clonogenic and comet assays, for studying the cellular and molecular aspects, respectively).…”

“…NVP-BEZ235 is also an effective radiosensitizer that inhibits ataxia telangiectasia mutated ( ATM ) and DNA-PK catalytic subunits ( DNAPKcs ), arrests cell cycle, and induces apoptosis [18][19][20] . Moreover, one of the stem-like cell lines, A172 cells, can be induced to undergo differentiation by pretreatment with NVP-BEZ235 and can produce a significant decrease in tumorigenicity when transplanted either subcutaneously or intracranially [21,22] . Nevertheless, the effect of combined IR and NVP-BEZ235 treatments on the radioresistance of GSCs has not yet been reported.…”

Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling

“…Akt/mTOR signaling is rapidly emerging as critical signaling for the regulation of stemness-related genes and T-IC maintenance (29). It was reported that inhibition of mTOR by rapamycin could lead to activation of Akt, resulting from abrogating the feedback inhibition mediated by activated mTOR pathway (30).…”

LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway

“…Thus, there is an urgent need to develop novel therapeutic approaches to cure this malignancy. As the molecular mechanisms of gliomas have gradually been clarified, improving chemotherapeutic methods is the key to combination treatment (3,(5)(6)(7)(8)(9)(10)(11). The therapeutic goal of chemotherapy is to trigger tumor-selective cell death.…”