Curcumin-induced downregulation of Axl receptor tyrosine kinase inhibits cell proliferation and circumvents chemoresistance in non-small lung cancer cells
Curcumin-induced downregulation of Axl receptor tyrosine kinase inhibits cell proliferation and circumvents chemoresistance in non-small lung cancer cells
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DOI：
10.3892/ijo.2015.3216
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发表时间：
2015-12-01
影响因子：
5.2
通讯作者：
Lee, Chuhee
中科院分区：
文献类型：
--
作者：
Kim, Kyung-Chan;Baek, Suk-Hwan;Lee, Chuhee
在发病率和死亡率方面，肺癌仍然位居首位。在本研究中，我们证明了姜黄素对Ax1受体酪氨酸激酶(RTK)表达和激活的影响，RTK在细胞存活、增殖和抗凋亡中起重要作用。姜黄素对非小细胞肺癌(NSCLC)A549和H460细胞的作用。发现以剂量和时间依赖的方式降低Axl蛋白和mRNA水平。姜黄素也降低了AXL启动子活性，表明姜黄素在转录水平下调了AXL的表达。此外，与其配体GAS-6结合后，AXL的磷酸化作用被姜黄素取消，提示姜黄素对Gas6诱导的AXL活化有抑制作用。接下来，我们发现葫芦素对亲代A549和H460细胞及其对顺铂(A549/CISR和H460/CISR)和紫杉醇(A549/tr和H460/tr)耐药的变异体都有细胞毒作用。姜黄素可导致细胞存活率和克隆形成能力呈剂量依赖性下降。进一步观察到姜黄素对过表达Ax1蛋白的A549细胞的抗增殖作用减弱，而对H460细胞的抑制作用增强，证实姜黄素通过下调Ax1蛋白的表达而抑制细胞增殖。此外，姜黄素还可诱导亲本H460细胞及耐药细胞H460/CISR和H460/TR中细胞周期蛋白依赖蛋白p21的表达和X-连锁凋亡抑制蛋白(XIAP)的表达。综上所述，我们的数据表明Axl RTK是姜黄素的一个新的靶点，通过它在亲本和化疗耐药的NSCLC细胞中发挥抗增殖作用。
Lung cancer is still in the first place in terms of both incidence and mortality. In the present study, we demonstrated the effect of curcumin, a phytochemical of the plant Curcuma longa, on expression and activation of Axl receptor tyrosine kinase (RTK) which plays an important role in cell survival, proliferation and anti-apoptosis. Curcumin treatment of non-small cell lung cancer (NSCLC) A549 and H460 cells, was. found to decrease Axl protein as Well as mRNA levels in a dose- and time-dependent manner. Axl promoter activity was also reduced by curcumin, indicating that curcumin down-regulates Axl expression at the transcriptional level. Moreover, Axl phosphorylation in response to binding of its ligand, Gas 6, was abrogated by curcumin, suggesting the inhibitory effect of curcumin on Gas6-induced Axl activation. We next found cytotoxic effect of cucumin on both the parental A549 and H460 cells, and their variants which are resistant to cisplatin (A549/CisR and H460/CisR) and paclitaxel (A549/TR and H460/TR). Exposure of these cells to curcumin resulted in dose-dependent decline of cell viability and clonogenic ability. It is further observed that the anti-proliferative effect of curcumin on A549 cells overexpressing Axl protein was reduced, while that on H460 cells transfected Axl specific siRNA was augmented, confirming that curcumin inhibits cell proliferation via downregulation of Axl expression. In addition, curcumin was found to cause the induction of p21, a cyclin-dependent kinase inhibitor, and reduction of X-linked inhibitor of apoptosis protein (XIAP), an anti-apoptotic molecule, in parental H460 cells as well as chemoresistant cells, H460/CisR and H460/TR. Taken together, our data imply that Axl RTK is a novel target of curcumin through which it exerts anti-proliferative effect in both parental and chemoresistant NSCLC cells.