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Int. J. Mol. Sci. 2017, 18(3), 529; doi:10.3390/ijms18030529

RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells

Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA
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Academic Editor: Carsten Stephan
Received: 22 January 2017 / Revised: 15 February 2017 / Accepted: 20 February 2017 / Published: 1 March 2017
(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer)
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Abstract

The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (HPC1) to RNASEL. To date, there is no correlation of viral infections with prostate cancer, suggesting that RNase L may play additional roles in tumor suppression. Here, we demonstrate a role of RNase L as a suppressor of androgen receptor (AR) signaling, cell migration and matrix metalloproteinase activity. Using RNase L mutants, we show that its nucleolytic activity is dispensable for both AR signaling and migration. The most prevalent HPC1-associated mutations in RNase L, R462Q and E265X, enhance AR signaling and cell migration. RNase L negatively regulates cell migration and attachment on various extracellular matrices. We demonstrate that RNase L knockdown cells promote increased cell surface expression of integrin β1 which activates Focal Adhesion Kinase-Sarcoma (FAK-Src) pathway and Ras-related C3 botulinum toxin substrate 1-guanosine triphosphatase (Rac1-GTPase) activity to increase cell migration. Activity of matrix metalloproteinase (MMP)-2 and -9 is significantly increased in cells where RNase L levels are ablated. We show that mutations in RNase L found in HPC patients may promote prostate cancer by increasing expression of AR-responsive genes and cell motility and identify novel roles of RNase L as a prostate cancer susceptibility gene. View Full-Text
Keywords: RNase L; androgen receptor; filamin A; prostate cancer RNase L; androgen receptor; filamin A; prostate cancer
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Dayal, S.; Zhou, J.; Manivannan, P.; Siddiqui, M.A.; Ahmad, O.F.; Clark, M.; Awadia, S.; Garcia-Mata, R.; Shemshedini, L.; Malathi, K. RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells. Int. J. Mol. Sci. 2017, 18, 529.

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