Androgen receptor dampens tissue factor expression via NF-κB and EGR1

5 years ago

Androgen receptor dampens tissue factor expression via NF-κB and EGR1

Ulrike Resch, Alice Assinger, Manuel Salzmann, Lena Hell, Bastian Hoesel, José Basílio, Johannes A. Schmid, Bernhard Moser, Marion Mussbacher, Nigel Mackman, Burak Dikorman, Hannah Paar, Johannes Thaler

Background Prostate cancer is one of the leading causes of cancer death in men. Advanced prostate cancer is usually treated by androgen deprivation therapy (ADT), which aims at diminishing circulating testosterone to reduce cancer growth. There is growing evidence that ADT can increase the rate of venous thromboembolism (VTE) in prostate cancer patients. The tissue factor (TF) gene is one of the most important mediators of coagulation and VTE, but so far there is limited data on androgen receptor (AR) mediated TF gene expression. Objectives To characterize AR mediated TF regulation in vitro and in vivo Methods We used the androgen dependent prostate cancer cell lines LNCaP and MyC-CaP to test whether TF expression is regulated by the AR. Furthermore, we cloned the TF promoter into a luciferase reporter vector to identify the transcription factor binding sites that mediate TF regulation downstream of the AR. Finally, we used castration experiments in mice to characterize AR mediated TF regulation in vivo. Results TF is directly regulated by the AR. In LNCaP cells, NF-κB signaling and EGR1 mediate TF expression. Using castration experiments in mice, we could detect an upregulation of TF and EGR1 mRNA and protein expression in prostate epithelial cells. Conclusion AR is crucial for dampening of TF expression, which could be important for increased TF expression and TF positive microvesicle release in androgen deprived prostate cancer patients.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/jth.13971