RNase L is a negative regulator of cell migration
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Shuvojit Banerjee1, Geqiang Li1,*, Yize Li2, Christina Gaughan1, Danika Baskar1, Yvonne Parker3, Daniel J. Lindner3, Susan R. Weiss2, Robert H. Silverman1
1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
2Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
3Translational Hematology and Oncology Research,Taussig Cancer Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
*Current address: Abpro, 65 Cummings Park Drive, Woburn, MA
Robert Silverman, e-mail: [email protected]
Keywords: RNase L, migration, metastasis, FAK, prostate cancer
Received: August 07, 2015 Accepted: October 14, 2015 Published: October 27, 2015
RNase L is a regulated endoribonuclease that functions in the interferon antiviral response. Activation of RNase L by 2’, 5’-oligoadenylates has been linked to apoptosis, autophagy and inflammation. Genetic studies have also suggested the possible involvement of the RNase L gene (RNASEL) on chromosome 1q25.3 in several types of cancer. Here we report that ablation of RNase L in human prostate cancer PC3 cells by CRISPR/Cas9 gene editing technology enhanced cell migration as determined both by transwell assays and scratch wound healing assays. In addition, RNase L knockdown by means of RNAi increased migration of PC3 and DU145 cells in response to either fibronectin or serum stimulation, as did homozygous disruption of the RNase L gene in mouse embryonic fibroblasts. Serum or fibronectin stimulation of focal adhesion kinase (FAK) autophosphorylation on tyrosine-397 was increased by either knockdown or ablation of RNase L. In contrast, a missense mutant RNase L (R667A) lacking catalytic activity failed to suppress cell migration in PC3 cells. However, a nuclease-inactive mutant mouse RNase L (W630A) was able to partially inhibit migration of mouse fibroblasts. Consistent with a role for the catalytic activity of RNase L, transfection of PC3 cells with the RNase L activator, 2’, 5’-oligoadenylate, suppressed cell migration. RNase L knockdown in PC3 cells enhanced tumor growth and metastasis following implantation in the mouse prostate. Our results suggest that naturally occurring mutations in the RNase L gene might promote enhanced cell migration and metastasis.
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