Wang Xiaona, Xue Qiang, Wu Liangliang, Wang Baogui, Liang Han
Department of Gastric Cancer Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin's Clinical Research Center for Cancer China.
FEBS Open Bio. 2018 Mar 23;8(5):732-742. doi: 10.1002/2211-5463.12404. eCollection 2018 May.
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.
达沙替尼是一种酪氨酸激酶抑制剂，已被批准用于白血病的一线治疗，也已被评估用于许多其他癌症。然而，其在胃癌（GC）中的作用仍不清楚。因此，本研究的目的是探讨达沙替尼如何抑制GC细胞的生长以及与化疗药物相互作用。结果表明，在达沙替尼存在的情况下，GC细胞的增殖减少，凋亡增加，并且Fas相关死亡结构域蛋白和半胱天冬酶-8对达沙替尼诱导的GC细胞凋亡至关重要。此外，我们发现达沙替尼增加了GC细胞中死亡受体5（DR5）的表达。达沙替尼增强了肿瘤坏死因子相关凋亡诱导配体（TRAIL）在GC细胞中诱导的凋亡。此外，DR5表达的增加促进了达沙替尼诱导的凋亡；达沙替尼诱导的DR5表达增加是由CCAAT/增强子结合蛋白同源蛋白（CHOP）介导的。此外，达沙替尼还与TRAIL协同作用，通过DR5在GC细胞中诱导凋亡。我们的结果表明，达沙替尼通过上调GC中CHOP依赖性DR5表达促进TRAIL介导的凋亡，提示DR5诱导可作为达沙替尼敏感性的指标。
