Abstract
R428, a selective small molecule Axl inhibitor, is known to have anti-cancer effects, such as inhibition of invasion and proliferation and induction of cell death in cancer cells. The Axl receptor tyrosine kinase is highly expressed in cancer cells and the level of Axl expression is associated with survival, metastasis, and drug resistance of many cancer cells. However, the effect of Axl inhibition on overcoming anti-cancer drugs resistance is unclear. Therefore, we investigated the capability of Axl inhibition as a therapeutic agent for the induction of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) sensitivity. In this study, R428 markedly sensitized cancer cells to TRAIL-induced apoptotic cell death, but not in normal human skin fibroblast (HSF) and human umbilical vein cells (EA.hy926). Moreover, knockdown of Axl by siRNA also increased TRAIL-induced apoptosis. R428 decreased c-FLIP proteins levels via induction of miR-708 expression and survivin protein levels at the post-translational level, and we found that knockdown of Axl also decreased both c-FLIP and survivin protein expression. Overexpression of c-FLIP and survivin markedly inhibited R428 plus TRAIL-induced apoptosis. Furthermore, R428 sensitized cancer cells to multiple anti-cancer drugs-mediated cell death. Our results provide that inhibition of Axl could improve sensitivity to TRAIL through downregulation of c-FLIP and survivin expression in renal carcinoma cells. Taken together, Axl may be a tempting target to overcome TRAIL resistance.
Highlights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of most tumor cells, but not of normal cells [1,2]
We show that inhibition of Axl overcomes TRAIL resistance through downregulation of c-FLIP and survivin expression in cancer cells
We found that R428 markedly decreased phospho (p)-Axl expression (Figure 1A)
Summary
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of most tumor cells, but not of normal cells [1,2]. Many cancer cells reveal the resistance of TRAIL through increased decoy receptors and decreased death receptor (DR), anti-apoptotic Bcl-2 and IAP family proteins, and c-FLIP [3,4,5]. Due to the defects of cancer therapy using TRAIL, many studies suggest a way to overcome TRAIL resistance through modulation of protein expression, which are related with anti-cancer drugs resistance. Combined treatment with chemotherapeutic agent is one of the ways to increase the sensitivity to anti-cancer drugs [6]. Identification of TRAIL sensitizers is needed to propose a way to overcome TRAIL resistance.
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