CYP1B1 induces tumorigenic metastasis through promotion of uPAR and subsequently activation of uPAR signaling via regulation of MDM2‐uPAR system

Abstract

Human CYP1B1 is known as a major metabolizer for estrogen and shows tumor‐specific hyper‐expression. To explore the role of CYP1B1 on metastasis of human cancer cells, we studied the effects of CYP1B1 inhibition and activation in MCF‐10A, MCF‐7, MDA‐MB‐231, and HeLa cells. CYP1B1 significantly induced expression of urokinase‐type plasminogen activator receptor (uPAR) as well as uPA. Treatment with DMBA, a well‐known CYP1B1 inducer, enhanced uPAR expression while CYP1B1 siRNA and TMS (tetramethoxystilbene), a specific CYP1B1 inhibitor, suppressed uPAR. We also found that CYP1B1 activated uPAR signaling through regulation of related factors including integrin β1 and α5. Interestingly, uPAR overexpression only caused a significant increase of integrin β1 and α5 in protein levels, indicating protein degradation may play an important role in regulating integrin protein level. Surprisingly, CYP1B1 down‐regulated p53 expression through MDM2 activation and nutlin‐3a, an inhibitor for MDM2, blocked the promoting effects of DMBA on uPAR, which explains that CYP1B1 induced uPAR expression through regulation of MDM2‐p53 system. Taken together, our data suggest that CYP1B1 promotes cancer cell metastasis via activating uPAR pathway which is one of the targets of p53 signaling.Support or Funding InformationThis research was supported by a National Research Foundation of Korea (NRF) funded by the Korean government (MSIP) (NRF‐2015R1A5A1008958).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.