p53-Mediated PI3K/AKT/mTOR Pathway Played a Role in Ptox^Dpt-Induced EMT Inhibition in Liver Cancer Cell Lines

Abstract

Epithelial-mesenchymal transition (EMT) involves metastasis and drug resistance; thus, a new EMT reversing agent is required. It has shown that wild-type p53 can reverse EMT back to epithelial characteristics, and iron chelator acting as a p53 inducer has been demonstrated. Moreover, recent study revealed that etoposide could also inhibit EMT. Therefore, combination of etoposide with iron chelator might achieve better inhibition of EMT. To this end, we prepared di-2-pyridineketone hydrazone dithiocarbamate S-propionate podophyllotoxin ester (Ptox^Dpt) that combined the podophyllotoxin (Ptox) structural unit (etoposide) with the dithiocarbamate unit (iron chelator) through the hybridization strategy. The resulting Ptox^Dpt inherited characteristics from parent structural units, acting as both the p53 inducer and topoisomerase II inhibitor. In addition, the Ptox^Dpt exhibited significant inhibition in migration and invasion, which correlated with downregulation of matrix metalloproteinase (MMP). More importantly, Ptox^Dpt could inhibit EMT in the absence or presence of TGF-<i>β</i>1, concomitant to the ROS production, and the additional evidence revealed that Ptox^Dpt downregulated AKT/mTOR through upregulation of p53, indicating that Ptox^Dpt induced EMT inhibition through the p53/PI3K/AKT/mTOR pathway.