Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with potential anticancer effect, but innate and adaptive TRAIL resistance in majority of cancers limit its clinical application. Karyopherin β1 (KPNB1) inhibition in cancer cells has been reported to abrogate the nuclear import of TRAIL receptor DR5 and facilitate its localization on the cell surface ready for TRAIL stimulation. However, our study reveals a more complicated mechanism. Genetic or pharmacological inhibition of KPNB1 potentiated TRAIL-induced apoptosis selectively in glioblastoma cells mainly by unfolded protein response (UPR). First, it augmented ATF4-mediated DR5 expression and promoted the assembly of death-inducing signaling complex (DISC). Second, it freed Bax and Bak from Mcl-1. Third, it downregulated FLIPL and FLIPS, inhibitors of caspase-8 cleavage, partly through upregulating ATF4–induced 4E-BP1 expression and disrupting the cap-dependent translation initiation. Meanwhile, KPNB1 inhibition-induced undesirable autophagy and accelerated cleaved caspase-8 clearance. Inhibition of autophagic flux maintained cleaved caspase-8 and aggravated apoptosis induced by KPNB1 inhibitor plus TRAIL, which were abolished by caspase-8 inhibitor. These results unveil new molecular mechanism for optimizing TRAIL-directed therapeutic efficacy against cancer.
Highlights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belongs to the tumor necrosis factor superfamily of cytokines and is involved in inflammation and immunosurveillance
These results suggest that KPNB1 inhibition synergizes with TRAIL to selectively induce apoptosis in glioblastoma cells
Bioinformatics analysis indicated that KPNB1 mRNA expression had moderate negative correlation with that of ATF4 in glioblastoma multiforme but not low grade glioma (Supplementary Fig. S7). These results suggest that KPNB1 inhibition upregulates 4E-BP1 by ATF4, which reduces the capdependent translation of FLIPS and TRAIL resistance
Summary
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belongs to the tumor necrosis factor superfamily of cytokines and is involved in inflammation and immunosurveillance. It is expressed in both normal and tumor cells. TRAIL induces apoptosis by engaging its functional receptors DR4 (TRAIL-R1) and DR5 (TRAILR2). Upon TRAIL stimulation, TRAIL receptors undergo homotrimerization and recruit Fas-associated protein with death domain (FADD). Of this death-inducing signaling complex (DISC) promotes caspase-8 processing and Clinical trials revealed the safety but disappointed clinical benefits of TRAIL-based therapies[2,3]. Multiple factors in TRAIL receptor signaling determine TRAIL responsiveness, including the expression, localization, and clustering of TRAIL receptors, the assembly and distribution of DISC and the expression of Bcl-2 family proteins and inhibitors of apoptosis proteins[1,4]
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