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PLoS One. 2013 Aug 9;8(8):e70987. doi: 10.1371/journal.pone.0070987. eCollection 2013.

MicroRNA-185 and 342 inhibit tumorigenicity and induce apoptosis through blockade of the SREBP metabolic pathway in prostate cancer cells.

Author information

1
Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Abstract

MicroRNA (miRNA or miR) inhibition of oncogenic related pathways has been shown to be a promising therapeutic approach for cancer. Aberrant lipid and cholesterol metabolism is involved in prostate cancer development and progression to end-stage disease. We recently demonstrated that a key transcription factor for lipogenesis, sterol regulatory element-binding protein-1 (SREBP-1), induced fatty acid and lipid accumulation and androgen receptor (AR) transcriptional activity, and also promoted prostate cancer cell growth and castration resistance. SREBP-1 was overexpressed in human prostate cancer and castration-resistant patient specimens. These experimental and clinical results indicate that SREBP-1 is a potential oncogenic transcription factor in prostate cancer. In this study, we identified two miRNAs, miR-185 and 342, that control lipogenesis and cholesterogenesis in prostate cancer cells by inhibiting SREBP-1 and 2 expression and down-regulating their targeted genes, including fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR). Both miR-185 and 342 inhibited tumorigenicity, cell growth, migration and invasion in prostate cancer cell culture and xenograft models coincident with their blockade of lipogenesis and cholesterogenesis. Intrinsic miR-185 and 342 expression was significantly decreased in prostate cancer cells compared to non-cancerous epithelial cells. Restoration of miR-185 and 342 led to caspase-dependent apoptotic death in prostate cancer cells. The newly identified miRNAs, miR-185 and 342, represent a novel targeting mechanism for prostate cancer therapy.

PMID:
23951060
PMCID:
PMC3739799
DOI:
10.1371/journal.pone.0070987
[Indexed for MEDLINE]
Free PMC Article

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