Non-receptor tyrosine kinase Etk regulation of drug resistance in small-cell lung cancer

Epithelial and endothelial tyrosine kinase (Etk), also known as Bmx (bone marrow X kinase), plays an important role in the apoptosis of epithelial cells. The aim of this study was to investigate whether Etk is involved in the chemoresistance of small cell lung cancer (SCLC) and to correlate the drug resistance associated proteins such as bcl-2, bcl-XL and p53. Drug-resistant small lung cancer cells (H69AR) which were originally developed by ADM and which demonstrated multi-drug resistance to chemotherapeutic agents were used in the study. Western blot analysis revealed that H69AR cells over-expressed the proteins Etk and bcl-XL, but not bcl-2 and p53 when compared to parent H69 cells. Knockdown of Etk expression by Etk-specific small interfering RNA sensitised H69AR cells to chemotherapeutic drugs and inhibited bcl-XL expression but not bcl-2 and p53. Co-immunoprecipitation was performed to further evaluate the relationship between Etk and bcl-XL with anti-Etk and anti-phospho-Etk antibodies. The bcl-XL was accompanied with a robust increase of Etk and tyrosine phosphorylated Etk at Tyr-40 in H69AR cells. In conclusion, our results suggest that non-receptor tyrosine kinase Etk is involved in drug resistance to SCLC by mediating bcl-XL via Tyr(P)-40. The potential approach for downregulation of Etk activity on expression would be a novel, potentially clinically practical strategy for interfering with chemoresistance in SCLC.