Abstract. 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 nonsmall 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 downregulates Axl expression at the transcriptional level. Moreover, Axl phosphorylation in response to binding of its ligand, Gas6, 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.
IntroductionWorldwide, lung cancer is the most frequently diagnosed cancer and the leading cause of cancer deaths (1). Approximately 85-90% of lung cancer is non-small cell lung cancer (NSCLC) which is characterized by relatively low growth rate and poor responsiveness upon chemotherapy, compared to small cell lung cancer (SCLC) (2). Although platinum or taxol-based chemotherapy has been the standard treatment for NSCLC patients, the intrinsic and acquired resistances to these drugs are the major obstacles to achieve the successful long-term outcomes. To overcome the resistance, the second line or combination chemotherapy regimens have been used (3-5), but the overall survival benefits of various chemotherapies in NSCLC is not yet satisfactory.The large receptor tyrosine kinase (RTK) family in the human genome contains 58 RTKs and is divided into 20 subfamilies. One of the subfamilies is TAM family composed of three RTK members which are Tyro3 (also referred to Brt, Dtk, Rse, Sky or Tif ), Axl (also referred to Ark, Tyro7 or Ufo) and Mer (also referred to Eyk, Nyk or Tyro12) (6-9). Each of them has similar structural features, which are extracellular domains, two immunoglo...