Reversal of drug resistance in breast cancer cells by transglutaminase 2 inhibition and nuclear factor-κB inactivation

Induction of transglutaminase 2 (TGase 2) by epidermal growth factor (EGF) in human breast cancer cells increases their oncogenic potential and chemoresistance. The role of TGase 2 in the development of these tumor-related phenotypes remains to be elucidated, but it has been shown that expression of a dominant-negative form of TGase 2 reverses EGF-mediated chemoresistance in breast cancer cells. We examined several different breast cancer cell lines, representing both EGF receptor (EGFR)-positive and EGFR-negative breast cancers, and found that doxorubicin-resistant cells had a higher level of TGase 2 compared with doxorubicin-sensitive cells independent of the EGFR expression level. TGase 2 inhibition increased the chemosensitivity of drug-resistant cells, concomitant with a decrease in nuclear factor-κB (NF-κB) activity. Increasing the level of TGase 2 in drug-sensitive cells by transient transfection reduced the level of inhibitory subunit α of NF-κB (IκBα) and increased NF-κB activity in these cells. Inhibition of TGase 2 in drug-resistant cells by RNA interference increased the levels of IκBα, and this correlated with a shift in the accumulation of NF-κB from the nucleus to the cytosol. We recently showed that TGase 2 activated NF-κB through polymerization and depletion of free IκBα during inflammation. Therefore, increased expression of TGase 2 and subsequent activation of NF-κB may contribute to drug resistance in breast cancer cells independently of EGF signaling.