Department of Biochemistry and Molecular Pharmacology
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
© 2013 Cui et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
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.