Abstract
Dasatinib, a tyrosine kinase inhibitor, has been approved for first‐line treatment of leukemia and has also been evaluated for use in numerous other cancers. However, its role in gastric cancer (GC) remains unclear. Therefore, the aim of this study was to investigate how dasatinib suppresses the growth of GC cells and interacts with chemotherapeutic drugs. The results showed that, in the presence of dasatinib, proliferation of GC cells decreased and apoptosis increased, and that Fas‐associated death domain protein and caspase‐8 are essential to dasatinib‐induced cell apoptosis in GC. In addition, we found that dasatinib increased the expression of death receptor 5 (DR5) in GC cells. Dasatinib enhanced apoptosis induced by tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) in GC cells. Moreover, increased DR5 expression facilitated dasatinib‐induced apoptosis; the dasatinib‐induced increase in DR5 expression was mediated by CCAAT/enhancer‐binding protein homologous protein (CHOP). Furthermore, dasatinib also synergized with TRAIL to induce apoptosis via DR5 in GC cells. Our results show that dasatinib promoted TRAIL‐mediated apoptosis via upregulation of CHOP‐dependent DR5 expression in GC, suggesting that DR5 induction can be used as an indicator of dasatinib sensitivity.
Highlights
Our results show that dasatinib promoted tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via upregulation of CHOPdependent death receptor 5 (DR5) expression in gastric cancer (GC), suggesting that DR5 induction can be used as an indicator of dasatinib sensitivity
The results revealed that dasatinib sensitized TRAIL-mediated apoptosis via DR5 induction in a CCAAT/enhancer-binding protein homologous protein (CHOP)-dependent manner, suggesting that the inductive effect of DR5 may be used to evaluate the efficiency of dasatinib and other drugs for chemotherapy
We found that GC cell proliferation significantly decreased (Fig. 1A)
Summary
The results showed that, in the presence of dasatinib, proliferation of GC cells decreased and apoptosis increased, and that Fas-associated death domain protein and caspase-8 are essential to dasatinib-induced cell apoptosis in GC. Dasatinib enhanced apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in GC cells. Gastric cancer (GC) is the third leading cause of cancer-associated deaths and the fifth most common malignancy worldwide; its development and progression are considered to be multistep processes, which are thought to be affected by accumulated mutations in related genes [1,2,3]. Abbreviations ChIP, chromatin immunoprecipitation; CHOP, CCAAT/enhancer-binding protein homologous protein; DR, death receptor; ER, endoplasmic reticulum; FADD, Fas-associated death domain protein; GC, gastric cancer; shRNA, short hairpin RNA; siRNA, small interfering RNA; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TUNEL, terminal deoxynucleotidyl transferasemediated dUTP nick end labeling; z-VAD-fmk, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone
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