<i>N</i>‐arachidonoyl dopamine inhibits epithelial–mesenchymal transition of breast cancer cells through ERK signaling and decreasing the cellular cholesterol
Shreetama Bandyopadhayaya, Mikhail Akimov, R. C. Verma, Ankit Sharma, Divya Sharma, Gopal C. Kundu, N. M. Gretskaya, В. В. Безуглов, Chandi C. Mandal
Abstract
N-acyl dopamines (NADAs) are bioactive lipids of the endovanilloid family with known cytotoxicity for the cancer cells; however, the available data on the participation of the endovanilloids in epithelial-mesenchymal transition (EMT) and cancer stemness are controversial. This study unveils the inhibitory role of N-arachidonoyl dopamine (AA-DA), a typical representative of the NADA family, in breast cancer cell migration, EMT, and stemness. AA-DA treatment also led to a decrease in cholesterol biosynthesis gene expressions, and addition of exogenous cholesterol reverted these AA-DA-mediated inhibitory effects. Notably, AA-DA treatment inhibited the key regulatory gene of the cholesterol biosynthesis pathway, sterol regulatory element-binding protein 1 (SREBP1), with concurrent repression of the endoplasmic reticulum kinase 1/2 (ERK1/2) pathway. Furthermore, U0126, an ERK inhibitor, inhibited SREBP1 and decreased cellular cholesterol level, unwinding the molecular mechanism behind AA-DA-mediated anticancer activity. Thus, we, for the first time, revealed that AA-DA counteracts breast cancer EMT via inhibition of ERK signaling and cholesterol content.