Transglutaminase 2 promotes breast cancer cell autophagy by targeting p53/ mTOR axis

Breast cancer (BC) is the most common malignant tumor among women. There is a pressing demand to develop new therapeutic strategies for advanced BC. In this report, we investigated whether Transglutaminase 2 (TGM2) is involved in BC growth. Moreover, a high expression of TGM2 in BC was found to be correlated with a poor prognosis. Thus, TGM2 might be a prospective therapeutic target in BC. We examined if a small molecule inhibitor of TGM2, GK921, could suppress BC growth. GK921 inhibited TGM2 activity and induced autophagy-dependent cell death in BC cell lines. Additionally, we found that GK921 increased p53 levels, which decreased the expression of mTOR, a classical upstream regulator of autophagy. Finally, we found that down regulation of TGM2 using RNAi activated autophagy. Consistent with these findings, GK921 significantly suppressed breast tumor growth in mouse models, suggesting that TGM2 may be a potential therapeutic target for BC treatment.