Abstract
Background
Colorectal cancer (CRC) represents approximately 10% of all cancer cases and ranks as the second leading cause of cancer-related death. Existing clinical targeted therapies for CRC lack efficacy, highlighting the urgent need for identifying novel target sites.
Methods
Using the Kaplan-Meier Plotter analyzed the correlation between the expression level of NFATc1 and the prognosis/stage of CRC. Using Cell Viability Assay kit, flow cytometry, calculation of micronucleus and abnormal chromosome number, transwell system and Xenograft on nude mice, we detected the effects of NFATc1 on the cell viability, division, migration and tumor-forming ability of CRC cells. Using ChIP assay, site-directed mutagenesis and dual luciferase assay analyzed the mechanism of NFATc1 on MDM2-p53 loop. Tumor treatment with NIFE and oxaliplatin test the effect of NIFE on the anti-tumor effect of oxaliplatin.
Results
The expression level of NFATc1 in CRC tissues is significantly increased compared with that in adjacent tissues and NFATc1 expression level is closely correlated to the poor prognosis of CRC patients with advanced clinical stage. Silencing NFATc1 markedly decreased the viability, abnormal cell cycle, migration, and tumor-forming ability of CRC cells. Mechanistically, NFATc1 not only upregulate the expression of MDM2, but also disrupt the feedback activation of p53 on MDM2 by directly binding the p1 and p2 promoter regions of MDM2, thus blocking MDM2-p53 loop. Consequently, the high expression of NFATc1 leads to sustained MDM2 activation, and diminished p53 stability. Finally, nifedipine inhibited CRC tumors growth by inhibiting the NFATc1/MDM2 pathway, and significantly improve the anti-colorectal cancer effect of the clinical drug oxaliplatin.
Conclusions
NFATc1 impairs the MDM2-p53 feedback loop to drive colorectal cancer growth and Nifedipine inhibited CRC tumors growth by inhibiting the NFATc1/MDM2 pathway.