Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Amidines; Cell Cycle Checkpoints; Cell Line, Tumor; Colonic Neoplasms; Cyclin D; Cyclin E; Cyclin-Dependent Kinase 6; Enzyme Inhibitors; G1 Phase; Gene Expression Regulation, Neoplastic; Humans; Hydrolases; MicroRNAs; Protein Isoforms; Signal Transduction; Tumor Suppressor Protein p53
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Protein Arginine Deiminases (PADs) catalyze the post-translational conversion of peptidyl-Arginine to peptidyl-Citrulline in a calcium-dependent, irreversible reaction. Evidence is emerging that PADs play a role in carcinogenesis. To determine the cancer-associated functional implications of PADs, we designed a small molecule PAD inhibitor (called Chor-amidine or Cl-amidine), and tested the impact of this drug on the cell cycle. Data derived from experiments in colon cancer cells indicate that Cl-amidine causes a G1 arrest, and that this was p53-dependent. In a separate set of experiments, we found that Cl-amidine caused a significant increase in microRNA-16 (miRNA-16), and that this increase was also p53-dependent. Because miRNA-16 is a putative tumor suppressor miRNA, and others have found that miRNA-16 suppresses proliferation, we hypothesized that the p53-dependent G1 arrest associated with PAD inhibition was, in turn, dependent on miRNA-16 expression. Results are consistent with this hypothesis. As well, we found the G1 arrest is at least in part due to the ability of Cl-amidine-mediated expression of miRNA-16 to suppress its' G1-associated targets: cyclins D1, D2, D3, E1, and cdk6. Our study sheds light into the mechanisms by which PAD inhibition can protect against or treat colon cancer.
Rights and Permissions
Citation: PLoS One. 2013;8(1):e53791. doi: 10.1371/journal.pone.0053791. Epub 2013 Jan 7. Link to article on publisher's site
Cui, Xiangli; Witalison, Erin E.; Chumanevich, Alena P.; Chumanevich, Alexander A.; Poudyal, Deepak; Subramanian, Venkataraman; Schetter, Aaron J.; Harris, Curtis C.; Thompson, Paul R.; and Hofseth, Lorne J., "The induction of microRNA-16 in colon cancer cells by protein arginine deiminase inhibition causes a p53-dependent cell cycle arrest." (2013). Thompson Lab Publications. 29.