Inhibiting NFAT1 for breast cancer therapy: New insights into the mechanism of action of MDM2 inhibitor JapA

摘要

Transcription factor NFAT1 has been recently identified as a new regulator of the MDM2 oncogene. Targeting the NFAT1-MDM2 pathway represents a novel approach to cancer therapy. We have recently identified a natural product MDM2 inhibitor, termed JapA. As a specific and potent MDM2 inhibitor, JapA inhibits MDM2 at transcriptional and post-translational levels. However, the molecular mechanism remains to be fully elucidated for its inhibitory effects on MDM2 transcription. Herein, we reported that JapA inhibited NFAT1 and NFAT1-mediated MDM2 transcription, which contributed to the anticancer activity of JapA. Its effects on the expression and activity of NFAT1 were examined in various breast cancer cell lines in vitro and in MCF-7 and MDA-MB-231 xenograft tumors in vivo. The specificity of JapA in targeting NFAT1 and NFAT1-MDM2 pathway and the importance of NFAT1 inhibition in JapA's anticancer activity were demonstrated using NFAT1 overexpression and knockdown cell lines and the pharmacological activators and inhibitors of NFAT1 signaling. Our results indicated that JapA inhibited NFAT1 signaling in breast cancer cells in vitro and in vivo, which plays a pivotal role in its anticancer activity. JapA inhibited the nuclear localization of NFAT1, disrupted the NFAT1-MDM2 P2 promoter complex, and induced NFAT1 proteasomal degradation, resulting in the repression of MDM2 transcription. In conclusion, JapA is a novel NFAT1 inhibitor and the NFAT1 inhibition is responsible for the JapA-induced repression of MDM2 transcription, contributing to its anticancer activity. The results may pave an avenue for validating the NFAT1-MDM2 pathway as a novel molecular target for cancer therapy.