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

XIA XUE-MEI¹, LI DIAN-MING^1*, HU JUN-FENG¹, ZHANG YONG¹, GAO SHAN¹

Department of respiratory and critical care medicine, The First Affiliated Hospital of Bengbu Medical College

Objective: To study the effect of down-regulated Cx43 on acquired resistance of non-small lung cancer (NSCLC) cells to Gefitinib®, and explore its mechanisms.

Methods: Gefitinib®-resistant cells strain HCC827 GR were exposed gradually to increasing concentrations of Gefitinib®, 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® for HCC827 and HCC827 GR were 0.075 ± 0.013 and 10.67 ± 0.027 μmol/L, respec- tively, 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®, most likely due to the activation of PI3K / Akt signal pathway of Cx43 non- GJIC-dependent. Thus, mea- surement of levels of Cx43 is a useful guide during the treatment of NSCLC.