Abstract 2847: Human CYP1B1 induces cancer cell metastasis through Sp1-mediated activation of uPA-uPAR signaling pathway

Abstract

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. In addition, we revealed that CYP1B1 regulates uPAR through activation of Sp1 transcription factor. CYP1B1 and its enzymatic product, 4-OHE2, promote Sp1 expression levels in both mRNA and protein levels and subsequently Sp1 elevates the transcriptional activity of uPAR through binding to promoter region of uPAR. Taken together, our data suggest that CYP1B1 promotes cancer cell metastasis via activating uPAR pathway which is one of the targets of p53 and Sp1 signaling. Citation Format: Yeo-Jung Kwon, Sangyun Shin, Young-Jin Chun. Human CYP1B1 induces cancer cell metastasis through Sp1-mediated activation of uPA-uPAR signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2847.