Abstract
We previously observed that glioma cells are differentially sensitive to TRAIL-induced toxicity. Based on our observation that TRAIL-resistant glioma cell lines typically exhibited high levels of Akt activation, we hypothesized that inhibition of Akt signaling using the PI3 kinase inhibitor NVP-BKM120 could promote TRAIL-induced apoptosis in gliomas. We assessed this combination in established and primary cultured glioma cells. Combination treatment led to significant cellular death when compared to either drug alone, but had no effect in normal human astrocytes, and demonstrated activation of the caspase cascade. This enhanced apoptosis appears dependent upon the loss of mitochondrial membrane potential and the release of Smac/DIABLO, AIF and cytochrome c into the cytosol. The upregulation of Noxa and sequestration of Mcl-1 by Noxa were important factors for cell death. Knockdown of Noxa abrogated apoptosis and suggested dependency on Noxa in combination-induced apoptosis. BKM120 upregulated cell surface expression of death receptor 5 (DR5), but did not increase levels of the other major TRAIL receptor, death receptor 4 (DR4). This study demonstrates that antagonizing apoptosis-resistance pathways, such as the PI3/Akt pathway, in combination with death receptor activation, may induce cell death in TRAIL-resistant glioma.
Highlights
Malignant glioma is an aggressive brain tumor that responds poorly to conventional treatment modalities [1,2,3]
To demonstrate that sensitivity to this combination was not restricted to established cell lines, primary cultures were created from patients diagnosed with glioblastoma and were modestly sensitive to BKM120 or Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) as single agents, while the combination induced apoptosis (Fig. 2A)
Having validated the hypothesis that inhibition of Akt signaling via BKM120 can promote TRAIL activity, we examined potential mechanisms involved, including promotion of caspase cleavage and activation of the mitochondrial apoptotic pathway
Summary
Malignant glioma is an aggressive brain tumor that responds poorly to conventional treatment modalities [1,2,3]. Gliomas demonstrate multiple modes of resistance and single-agent therapy has proven ineffective in treatment of malignant. While most human cancer cell lines express death receptors for Apo2L/TRAIL, many cancer types have proven resistant to TRAIL-induced cellular death [14,15,16]. Among others, have shown that many malignant gliomas are TRAIL resistant, despite expression of TRAIL receptors [17,18,19] and aberrance in the NF-κB, protein kinase C, Bcl-2 and Akt pathways have all been implicated in TRAIL resistance in glioma [19,20,21]. Akt pathway activation, which can occur secondary to PTEN deletion and/or PIK3CA mutations, is common in malignant glioma [22]
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