AXL mediates TRAIL resistance in esophageal adenocarcinoma.

Abstract

The overexpression of AXL receptor tyrosine kinase is a frequent finding that has been associated with poor prognosis in esophageal adenocarcinoma (EAC). As the majority of EAC are intrinsically resistant to DNA-damaging therapies, an alternative therapeutic approach based on the activation of death receptors may be warranted. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been evaluated in clinical trials and found promising as anticancer agent with mild side effects; unfortunately, resistance to TRAIL remains a major clinical problem. Herein, we explored the role of AXL in TRAIL resistance and elucidated the underlying mechanism. Overexpression of AXL in OE33 and OE19 cells promoted cell survival and attenuated TRAIL-induced cellular and molecular markers of apoptosis. In contrast, knockdown of endogenous AXL sensitized FLO-1 cells to TRAIL. The mechanism by which AXL regulates TRAIL resistance was examined. Protein and mRNA expression of DR4 and DR5 death receptors was not downregulated by AXL. In addition, the possible involvement of FLICE-inhibitory protein (FLIP) in regulating the interaction of caspase-8 with Fas-associated death domain protein (FADD) was excluded, as AXL did not enhance FLIP expression or FLIP/FADD association. Alternatively, protein association of AXL with DR5, independent of TRAIL, was confirmed, suggesting that AXL could regulate DR5 receptor activity. The AXL/DR5 association had no negative effect on TRAIL-induced interaction with FADD. However, the AXL/DR5 interaction blocked the recruitment of caspase-8 to the death-inducing signal complex (DISC). Collectively, our findings uncover a novel mechanism of TRAIL resistance mediated by AXL through regulation of the DISC and provide strong evidence that AXL could be exploited as a therapeutic target to circumvent TRAIL resistance.

• Authors: Jun Hong, Abbes Belkhiri
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 15 Issue 3 Pg. 296-304 (Mar 2013) ISSN: 1476-5586 [Electronic] United States
• PMID: 23479507 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Death Domain Receptor Signaling Adaptor Proteins
• Proto-Oncogene Proteins
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• Receptor Protein-Tyrosine Kinases
• Caspases
• Axl Receptor Tyrosine Kinase
• AXL protein, human

Topics

• Adenocarcinoma (genetics)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Survival (genetics)
• Death Domain Receptor Signaling Adaptor Proteins (metabolism)
• Drug Resistance, Neoplasm
• Enzyme Activation (drug effects)
• Esophageal Neoplasms (genetics)
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Humans
• Protein Binding
• Proto-Oncogene Proteins (genetics, metabolism)
• Receptor Protein-Tyrosine Kinases (genetics, metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Axl Receptor Tyrosine Kinase