MECHANISMS INVOLVED IN THE EFFECT OF DOWN-REGULATED CX43 ON ACQUIRED RESISTANCE OF NON-SMALL CELL LUNG CANCER CELLS TO GEFITINIB®

Objective: To study the effect of down-regulated Cx43 on acquired resistance of non-small lung cancer (NSCLC) cells to Gefitinib (R), and explore its mechanisms. Methods: Gefitinib (R) - resistant cells strain HCC827 GR were exposed gradually to increasing concentrations of Gefitinib (R), and the IC50 value of the drug was determined by MTT assay. The Cx43 mRNA expression was measured using RT-PCR, while the protein and phosphorylated Akt (p-Akt) levels were determined with Western blot. Immunofluorescence technique was used for the analysis of the Cx43 cells. Results: The IC50 values of Gefitinib (R) for HCC827 and HCC827 GR were 0.075 +/- 0.013 and 10.67 +/- 0.027 mu mol/L, respectively, and differed significantly (p < 0.05). The expression levels of mRNA and protein of Cx43 in HCC827 GR were significantly lower than those of HCC827 (p < 0.05), while the protein level of p-Akt was significantly increased (p < 0.05). When LT294002, the specific inhibitor of PI3K was added to HCC827 GR, the protein expression level of p-Akt was significantly reduced (p < 0.05), while that of Cx43 was significantly increased (p < 0.01). Conclusion: The down-regulation of Cx43 in the cytoplasm of patients with NSCLC is associated with acquired resistance of NSCLC cells to Gefitinib (R), most likely due to the activation of PI3K / Akt signal pathway of Cx43 non-GJIC-dependent. Thus, measurement of levels of Cx43 is a useful guide during the treatment of NSCLC.