Abstract
In Response: In their Letter, Kyritsis et al. discussed the interesting question of the contribution of up-regulation of the apoptosis-inducing tumor necrosis factor–related apoptosis inducing ligand (TRAIL) receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), to the sensitization of tumor cells to TRAIL
Highlights
In Response: In their Letter, Kyritsis et al discussed the interesting question of the contribution of up-regulation of the apoptosis-inducing tumor necrosis factor – related apoptosis inducing ligand (TRAIL) receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), to the sensitization of tumor cells to TRAILinduced apoptosis by chemotherapeutic drugs
This result pointed to mechanisms of TRAIL resistance in these tumor cells which were independent of TRAIL death receptor expression
As emphasized by Puduvalli et al, PKB/Akt, which is an important survival signal, has been shown to modulate cFLIP expression in different tumor cells [3] and, we found that downregulation of cFLIP alone was sufficient to sensitize tumor cells to TRAIL [2, 4]
Summary
In Response: In their Letter, Kyritsis et al discussed the interesting question of the contribution of up-regulation of the apoptosis-inducing tumor necrosis factor – related apoptosis inducing ligand (TRAIL) receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), to the sensitization of tumor cells to TRAILinduced apoptosis by chemotherapeutic drugs. They showed that inhibition of PKB/Akt sensitized cells to TRAILinduced death [1] This is in line with our data from primary glioma cells which displayed considerable TRAIL resistance despite TRAIL-R2 expression and proper TRAIL death-inducing signaling complex formation upon receptor triggering [2]. Whereas overcoming the intracellular TRAIL blockade is indispensable for TRAIL sensitization, the chemotherapy-induced increase in TRAIL death receptors is not necessary for but could contribute to TRAIL sensitization [2, 4, 8, 9, 13] In this context, it would be quite interesting to test whether a cell line with a moderate increase in TRAIL-R2 surface expression, comparable to the level achieved by chemotherapeutic drug treatment, e.g., by carefully fine-tuned stable overexpression, would be sufficient to confer TRAIL sensitivity to primary glioma cells.
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