The response of leukemia cells to Apo2L/TRAIL: Characterization of resistance mechanisms and identification of strategies for overcoming resistance
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Targeting the death receptors on tumor cells with Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) has stimulated great interest among cancer researchers because of its ability to kill a broad spectrum of human malignant cells while sparing normal cells. However, some tumor cells, including leukemia cells, exhibit resistance to this promising therapeutic molecule. The goal of this research is to elucidate the mechanism(s) underlying resistance of tumor cells to TRAIL with a focus on leukemia cells and with this information, attempt to identify possible strategies to overcome resistance. To gain a better understanding of the basis for resistance of leukemia cells to Apo2L/TRAIL, several resistant HL60 clones were developed and isolated from parental HL60 cells using selection with Apo2L/TRAIL. In the case of the highly resistant clones, the level of the cell surface receptor DR4, but not DR5, was significantly decreased, indicating that cell surface DR4 plays a crucial role in determining the sensitivity to Apo2L/TRAIL. However, these cells did undergo apoptosis in response to histidine-tagged TRAIL, suggesting differential contributions of DR4 and DR5 in the response to different forms of TRAIL. In the completely resistant clones, a novel Leu 22 [arrow right] Phe 22 point mutation in the caspase-8 gene was associated with the loss of caspase-8 protein expression. These results demonstrate that cells within a tumor can develop resistance to TRAIL by diverse mechanisms. To study the potential of TRAIL-based therapeutics to improve the outcome of drug-resistant leukemia, the response of an adriamycin-resistant HL60 cell line (HL60/Adr) to TRAIL was investigated. It was observed that this cell line also exhibited resistance to Apo2L/TRAIL. This resistance was due to high constitutive NFκB activity in that the Apo2L/TRAIL resistance in HL60/Adr cells could be reversed using an NFκB-specific inhibitor. In contrast, blocking PI3K/Akt activity in HL60/Adr cells decreased the apoptotic response to Apo2L/TRAIL, indicating that PI3K/Akt is not an appropriate target to modulate Apo2L/TRAIL resistance. Taken together, this research will increase the understanding of why some patients' tumor cells respond to Apo2L/TRAIL while others fail to respond, and may contribute to the identification of new strategies to overcome Apo2L/TRAIL resistance.