title: RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells.
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) toRNASEL. 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.
authors.affiliation: Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Shubham.Dayal@rockets.utoledo.edu.
authors.forename: Shubham
authors.initials: S
authors.lastname: Dayal
authors.affiliation: Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Jun.zhou@rockets.utoledo.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Praveen.Manivannan@rockets.utoledo.edu.
authors.forename: Praveen
authors.initials: P
authors.lastname: Manivannan
authors.affiliation: Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Mohammad.Siddiqui@rockets.utoledo.edu.
authors.forename: Mohammad Adnan
authors.initials: MA
authors.lastname: Siddiqui
authors.affiliation: Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Omaima.Ahmad@rockets.utoledo.edu.
authors.forename: Omaima Farid
authors.initials: OF
authors.lastname: Ahmad
authors.affiliation: Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. clark.matt11@gmail.com.
authors.forename: Matthew
authors.initials: M
authors.lastname: Clark
authors.affiliation: Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Sahezeel.Awadia@rockets.utoledo.edu.
authors.forename: Sahezeel
authors.initials: S
authors.lastname: Awadia
authors.affiliation: Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Rafael.GarciaMata@utoledo.edu.
authors.forename: Rafael
authors.initials: R
authors.lastname: Garcia-Mata
authors.affiliation: Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Lirim.Shemshedini@utoledo.edu.
authors.forename: Lirim
authors.initials: L
authors.lastname: Shemshedini
authors.affiliation: Department of Biological Sciences, 2801 W. Bancroft St., University of Toledo, Toledo, OH 43606, USA. Malathi.Krishnamurthy@utoledo.edu.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Malathi
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011944:Receptors, Androgen; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D020782:Matrix Metalloproteinases
keywords: RNase L; androgen receptor; filamin A; prostate cancer