Reduction of transglutaminase 2 expression is associated with an induction of drug sensitivity in the PC-14 human lung cancer cell line.

Recently a role for transglutaminase 2 (TGase 2) in the drug resistance of cancer cells has been suggested, although the mechanism is unclear. In the present study, we observed that doxorubicin-resistant PC-14/ADR cells showed a ten-fold higher level of TGase 2 expression than drug-sensitive PC-14 cells. PC-14/ADR cells exhibited the classical multidrug resistance (MDR) phenotype, which was cross-resistant to vincristine, but not to cisplatin. The stepwise induction of resistance to doxorubicin and vincristine in PC-14 cells was accompanied by a gradual increase of TGase 2 expression, but this expression was not increased with induction of cisplatin resistance. To confirm the role of TGase 2 protein in the acquisition of drug resistance in PC-14 cells, the TGase 2 expression in PC-14/ADR cells was reduced by stable transfection with the antisense or ribozyme construct. In the clones showing reduced expression of TGase 2, lactate dehydrogenase released from drug-treated cells was increased in the presence of either MDR-related drugs (doxorubicin and vincristine) or a non-MDR-related drug (cisplatin). These data suggest that TGase 2 can play a role in the acquisition of drug resistance in PC-14 cells through a general cellular defense system other than the MDR-related system.