Activation of Src mediates acquired cisplatin resistance in human lung carcinoma cells.

Abstract

Cisplatin (CDDP) is the most effective chemotherapeutic drug against lung carcinoma. However, the emergence of resistant clones has severely limited its clinical application. We found that the cisplatin-resistant lung carcinoma cell line A549/CDDP had increased levels of the phosphorylated gap junction protein Cx43 and SRC tyrosine kinase, and low levels of total Cx43 protein and reduced gap junction formation. The SRC kinase inhibitor PP2 increased the expression of total Cx43 protein and enhanced cisplatin sensitivity, indicating that activated SRC kinase induces chemoresistance by decrease total Cx43 level. Furthermore, Cx43 gene silencing in the drug-resistant cell lines abrogated the sensitizing effect of PP2. Taken together, targeting SRC kinase by PP2 reverses cisplatin resistance by upregulating Cx43 protein levels, indicating a novel pathway of cisplatin resistance that may be amenable to therapeutic intervention.