Session: MP20: Prostate Cancer: Basic Research & Pathophysiology I
MP20-10: Enzalutamide Increases Prostate Cancer (PCa) Cell Invasion yet Decreases Bladder Cancer (BCa) Cell Invasion via Differentially Regulating the AR/circRNA-ARC1/miR-125b-2-3p or MiR-4736/PPARγ/MMP-9 Signals
Introduction: Androgen-deprivation therapy (ADT) is a standard treatment to prevent and shrink PCa growing. However, some patients undergoing ADT may finally develop to hormone-insensitive PCa. The underlying mechanisms haven't been fully elucidated. Here we found ADT-Enz led to increased PCa cell invasion, yet decreased BCa cell invasion. Our goal is to 1.reveal mechanisms of Enz induced hormone-insensitive PCa and find a potential combination therapy. 2. reveal mechanisms of ADT role in BCa and provide an evidence of applying ADT in BCa. Methods: The human PCa and BCa cells: C4-2, CWR22Rv1, T24 and TCC-SUP were used. Lentiviral plasmids were used to generate gene engineering tools. qPCR and Western blot were used to detect gene expressions. Invasion assay were applied to determine cancer cell invasion capability. Protein-DNA binding complexes were detected by Chromatin immunoprecipitation (ChIP) assays. PPARGC1B/PDK1 3'UTR regions were cloned into the psiCHECKTM-2 vector to assay the miRNA functions. Preclinical mouse PCa model was used to evaluate the anti-cancer efficacy of Enz and circRNA-ARC1 blockage. Results: Mechanistic dissection revealed that suppressing androgens/AR signals could result in differential alterations of the selective circular RNAs (circRNAs) as a result of differential endogenous AR transcription. A negative autoregulation in PCa, yet a positive autoregulation in BCa, as a result of differential binding of AR to different androgen-response elements (AREs) and a discriminating histone H3K4 methylation. Further mechanistic studies indicated that AR-encoded circRNA-ARC1 might sponge the availability of the miR-125b-2-3p and/or miR-4736 to impact the metastasis-related PPAR?/MMP-9 signals. The preclinical mouse model confirms in vitro cell lines data, showing that Enz treatment could increase PCa metastasis, which can be suppressed after iknockdown of circRNA-ARC1. Together, these results demonstrate that antiandrogen therapy with Enz treatment may differentially lead to promoting PCa cell invasion, yet decreasing BCa cell invasion. Conclusions: Our study is the first to reveal ADT-Enz treatment can promote PCa Cell Invasion yet decrease BCa cell Invasion via differentially regulating the AR/circRNA-ARC1/miR-125b-2-3p or MiR-4736/PPAR?/MMP-9 Signals. Furthermore, our findings may help in development of novel therapeutic approaches to increase the Enz efficacy with less adverse effects in patients with PCa, and providing an evidence of applying ADT in BCa. SOURCE OF Funding: This work was partially supported by URMC Urology Department Research fund and George H. Whipple Professorship Endowment.
