Activation of the TGF-81/EMT signaling pathway by claudin-1 overexpression reduces doxorubicin sensitivity in small cell lung cancer SBC-3 cells

Small-cell lung cancer (SCLC), which accounts for about 15 % of all lung cancers, progresses more rapidly than other histologic types and is rarely detected at an operable early stage. Therefore, chemotherapy, radiation therapy, or their combination are the primary treatments for this type of lung cancer. However, the tendency to acquire resistance to anticancer drugs is a severe problem. Recently, we found that an intercellular adhesion molecule, claudin (CLDN) 1, known to be involved in the migration and invasion of lung cancer cells, is involved in the acquisition of anticancer drug resistance. In the present study, we investigated the effect of CLDN1 on the anticancer-drug sensitivity of SCLC SBC-3 cells. Since epithelial-mesenchymal transition (EMT), which is involved in cancer cell migration and invasion, is well known for its involvement in anticancer-drug sensitivity via inhibition of apoptosis, we also examined EMT involvement in decreased anticancer-drug sensitivity by CLDN1. Sensitivity to doxorubicin (DOX) in SBC-3 cells was significantly decreased by CLDN1 overexpression. CLDN1 overexpression resulted in increased TGF-81 levels, enhanced EMT induction, and increased migratory potency of SBC-3 cells. The decreased sensitivity of SBC-3 cells to anticancer drugs upon TGF-81 treatment suggested that activation of the TGF-81/EMT signaling pathway by CLDN1 causes the decreased sensitivity to anticancer drugs and increased migratory potency. Furthermore, treatments with antiallergic agents tranilast and zoledronic acid, known EMT inhibitors, significantly mitigated the decreased sensitivity of CLDN1overexpressing SBC-3 cells to DOX. These results suggest that EMT inhibitors might effectively overcome reduced sensitivity to anticancer drugs in CLDN1-overexpressing SCLC cells.

Automated summary

This study investigated the effect of intercellular adhesion molecule CLDN1 on the anticancer drug sensitivity of small-cell lung cancer (SCLC) cells. It was found that overexpression of CLDN1 decreased the sensitivity of SCLC cells to anticancer drugs and enhanced their migratory capacity through the activation of the TGF-81/EMT signaling pathway. Treatment with EMT inhibitors showed potential in overcoming the reduced sensitivity to anticancer drugs in CLDN1-overexpressing SCLC cells.