The induction of microRNA-16 in colon cancer cells by protein arginine deiminase inhibition causes a p53-dependent cell cycle arrest.

Abstract

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.

• Authors: Xiangli Cui, Erin E Witalison, Alena P Chumanevich, Alexander A Chumanevich, Deepak Poudyal, Venkataraman Subramanian, Aaron J Schetter, Curtis C Harris, Paul R Thompson, Lorne J Hofseth
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e53791 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23308284 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amidines
• Cyclin D
• Cyclin E
• Enzyme Inhibitors
• MIRN16 microRNA, human
• MicroRNAs
• Protein Isoforms
• Tumor Suppressor Protein p53
• CDK6 protein, human
• Cyclin-Dependent Kinase 6
• Hydrolases
• Protein-Arginine Deiminases

Topics

• Amidines (chemical synthesis, pharmacology)
• Cell Cycle Checkpoints (drug effects, genetics)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cyclin D (genetics, metabolism)
• Cyclin E (genetics, metabolism)
• Cyclin-Dependent Kinase 6 (genetics, metabolism)
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• G1 Phase (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hydrolases (antagonists & inhibitors, genetics, metabolism)
• MicroRNAs (genetics, metabolism)
• Protein Isoforms (genetics, metabolism)
• Protein-Arginine Deiminases
• Signal Transduction
• Tumor Suppressor Protein p53 (agonists, genetics, metabolism)