miR-124 targets the androgen receptor transcript, acting as a tumor suppressor to broadly limit the growth of prostate cancer (CaP). In this study, we unraveled the mechanisms through which miR-124 acts in this setting.
miR-124 inhibited proliferation of CaP cells in vitro and sensitizes them to inhibitors of androgen receptor signaling (ARSIs). Notably, miR-124 could restore the apoptotic response of cells resistant to enzalutamide, a drug approved for the treatment of castration-resistant CaP. We employed xenograft models to examine the effects of miR-124 in vivo when complexed with polyethylenimine (PEI)-derived nanoparticles. Intravenous delivery of miR-124 was sufficient to inhibit tumor growth and to increase tumor cell apoptosis in combination with enzalutamide. Mechanistic investigations revealed that miR-124 directly downregulated AR splice variants AR-V4 and V7 along with EZH2 and Src, oncogenic targets that have been reported to contribute to CaP progression and treatment resistance. Taken together, our results offer a preclinical rationale to evaluate miR-124 for cancer treatment.
Cancer research. 2015 Nov 16 [Epub ahead of print]
Xu-Bao Shi, Aihong Ma, Lingru Xue, Meimei Li, Hao G Nguyen, Joy C Yang, Clifford G Tepper, Regina Gandour-Edwards, Christopher P Evans, Hsing-Jien Kung, Ralph W de Vere White
Department of Urology, University of California Davis. , Department of Dermatology, University of California Davis. , Department of Urology, University of California Davis. , Department of Urology, University of California, Davis. , Department of Urology, University of California, San Francisco. , Department of Urology, University of California at Davis. , Basic Science/Biochemistry and Molecular Medicine, UC Davis Cancer Center, UC Davis School of Mediicine. , Pathology and Laboratory Medicine, UC Davis Medical Center. , Department of Urology, University of California at Davis. , Biochemistry and Molecular Medicine, University of California, Davis. , Urology, University of California