miR-124 and Androgen Receptor Signaling Inhibitors Repress Prostate Cancer Growth by Downregulating Androgen Receptor Splice Variants, EZH2, and Src

Autor: Xu Bao Shi, Ralph W deVere White, Clifford G. Tepper, Regina F Gandour-Edwards, Hsing Jien Kung, Christopher P. Evans, Joy C. Yang, Hao G. Nguyen, Lingru Xue, Meimei Li, Ai Hong Ma
Rok vydání: 2015
Předmět:
Male
Cancer Research
Androgen
Mice
chemistry.chemical_compound
Prostate cancer
Receptors
2.1 Biological and endogenous factors
Protein Isoforms
Aetiology
Cancer
Tumor
Prostate Cancer
EZH2
Polycomb Repressive Complex 2
Gene Expression Regulation
Neoplastic
src-Family Kinases
Oncology
5.1 Pharmaceuticals
Receptors
Androgen
Development of treatments and therapeutic interventions
Signal transduction
Biotechnology
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
Urologic Diseases
Oncology and Carcinogenesis
Down-Regulation
Biology
Article
Cell Line
Downregulation and upregulation
Cell Line
Tumor
microRNA
Genetics
medicine
Animals
Humans
Enzalutamide
Enhancer of Zeste Homolog 2 Protein
Oncology & Carcinogenesis
Neoplastic
Prostatic Neoplasms
medicine.disease
Xenograft Model Antitumor Assays
Molecular biology
Androgen receptor
MicroRNAs
Gene Expression Regulation
chemistry
Cancer research
Zdroj: Cancer research, vol 75, iss 24
ISSN: 1538-7445
0008-5472
Popis: miR-124 targets the androgen receptor (AR) transcript, acting as a tumor suppressor to broadly limit the growth of prostate cancer. In this study, we unraveled the mechanisms through which miR-124 acts in this setting. miR-124 inhibited proliferation of prostate cancer cells in vitro and sensitized them to inhibitors of androgen receptor signaling. Notably, miR-124 could restore the apoptotic response of cells resistant to enzalutamide, a drug approved for the treatment of castration-resistant prostate cancer. We used xenograft models to examine the effects of miR-124 in vivo when complexed with polyethylenimine-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 prostate cancer progression and treatment resistance. Taken together, our results offer a preclinical rationale to evaluate miR-124 for cancer treatment. Cancer Res; 75(24); 5309–17. ©2015 AACR.
Databáze: OpenAIRE
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