Department of Thoracic Surgery, General Hospital of Chinese PLA, Beijing 100853, China.
Department of Thoracic Surgery, Shanxi Provincial Cancer Hospital, Taiyuan 030013, China.
Acta Biochim Biophys Sin (Shanghai). 2017 Oct 1;49(10):899-906. doi: 10.1093/abbs/gmx086.
Drug resistance greatly limits docetaxel efficiency in the treatment of non-small cell lung cancer (NSCLC). Dickkopf 4 (DKK4), a negative regulator of Wnt/β-catenin pathway, is believed to be involved in various human cancers; whereas the association of DKK4 with acquired docetaxel resistance in NSCLC remains unclear. In the present study, we investigated the involvement of DKK4 in the docetaxel-resistant human lung adenocarcinoma A549 (A549/DTX) cells. Our results showed that DKK4 expression was significantly increased in the A549/DTX cells compared with in the A549 cells, as well as in the culture supernatant of A549/DTX cells. DKK4 overexpression increased the resistance of A549 cells to docetaxel. DKK4-knockdown promoted inhibition of A549/DTX cell growth, and reduced the colony formation and invasion capacity of A549/DTX cells. Moreover, DKK4-knockdown promoted the pro-apoptotic effect of docetaxel characterized with caspase 3 activation and inhibition of BCL-2 expression in A549/DTX cells, which was possibly mediated by inducing the activation of c-Jun N-terminal kinase (JNK)-related signaling pathway. Thus, our results indicated that DKK4-knockdown promoted the cytotoxic and pro-apoptotic activity of A549/DTX cells, which suggests a critical role of DKK4 in docetaxel resistance of the A549 cells and provides the potential to combine docetaxel therapy with DKK4 depletion in treating NSCLC.
耐药性极大地限制了多西紫杉醇在非小细胞肺癌（NSCLC）治疗中的疗效。Dickkopf 4（DKK4）是 Wnt/β-catenin 通路的负调节剂，被认为参与了多种人类癌症；然而，DKK4 与 NSCLC 获得性多西紫杉醇耐药的关联尚不清楚。在本研究中，我们研究了 DKK4 在多西紫杉醇耐药的人肺腺癌细胞 A549（A549/DTX）中的作用。我们的结果表明，与 A549 细胞相比，A549/DTX 细胞中 DKK4 的表达显著增加，A549/DTX 细胞的培养上清液中也是如此。DKK4 过表达增加了 A549 细胞对多西紫杉醇的耐药性。DKK4 敲低促进了 A549/DTX 细胞的生长抑制，减少了 A549/DTX 细胞的集落形成和侵袭能力。此外，DKK4 敲低促进了 A549/DTX 细胞中多西紫杉醇的促凋亡作用，表现为 caspase 3 激活和 BCL-2 表达抑制，这可能是通过诱导 c-Jun N-末端激酶（JNK）相关信号通路的激活介导的。因此，我们的结果表明，DKK4 敲低促进了 A549/DTX 细胞的细胞毒性和促凋亡活性，这表明 DKK4 在 A549 细胞多西紫杉醇耐药中起关键作用，并为将多西紫杉醇治疗与 DKK4 耗竭相结合治疗 NSCLC 提供了潜力。
