Abstract
The mechanism of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in cancer cells is not fully understood. Here, we show that the Akt survival pathway plays an important role in TRAIL resistance in human cancer cells. Specifically, we found that TRAIL treatment activates the Akt survival pathway and that inhibition of this pathway by the PI3K inhibitor LY294002 or knockdown of Akt sensitizes resistant cancer cells to TRAIL. Since Akt is negatively regulated by the tumor suppressor PTEN, we examined the TRAIL sensitivity in PTEN knockdown mouse prostate epithelial cells and found that PTEN−/− cells are more resistant than PTEN+/+ cells while the sensitivity of PTEN+/− cells fell in between. Further, we showed that overexpression of a mutant PTEN confers TRAIL resistance in PTEN+/+ cells, supporting a role of PTEN in TRAIL sensitivity. In TRAIL resistant breast T47D cells, overexpression of the mutant PTEN further increased their resistance to TRAIL. Taken together, our data indicate that inactivation of functional PTEN and the consequent activation of the Akt pathway prevents TRAIL-induced apoptosis, leading to TRAIL resistance. Therefore, our results suggest that TRAIL resistance can be overcome by targeting PTEN or the Akt survival pathway in cancer cells.
Highlights
tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily that selectively induces apoptosis in cancer but not normal cells, making it an attractive agent for cancer therapy
A recent study showed that TRAIL sensitive non-small cell lung cancer (NSCLC) cells assemble death-inducting signaling complex (DISC) in lipid rafts of the plasma membrane that leads to caspase 8 activation, whereas non-raft DISC assembly leads to the recruitment of c-FLIP and RIP and the activation of the pro-survival signaling pathways such as NF-kB and ERK1/2 pathways [7]
These results suggest that increased activation of the Akt pathway via inactivation of PTEN plays an important role in TRAIL resistance
Summary
TRAIL (or Apo2L) is a member of the tumor necrosis factor superfamily that selectively induces apoptosis in cancer but not normal cells, making it an attractive agent for cancer therapy. Inhibition of the ERK and NF-kB pathways by their corresponding pharmacological inhibitors did not affect TRAIL sensitivity in OV90 cells (data not shown), indicating that the activation of these two pathways may not be important in TRAIL resistance in this cell line. We were able to show that restoration of PTEN expression renders PTEN2/2 cells sensitive to TRAIL induced apoptosis and growth inhibition whereas such effects were not observed in cells infected with control viruses (Fig. 5C).
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