title: 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: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America.
authors: Xiangli
authors: X
authors: Cui
authors: Erin E
authors: EE
authors: Witalison
authors: Alena P
authors: AP
authors: Chumanevich
authors: Alexander A
authors: AA
authors: Chumanevich
authors: Deepak
authors: D
authors: Poudyal
authors: Venkataraman
authors: V
authors: Subramanian
authors: Aaron J
authors: AJ
authors: Schetter
authors: Curtis C
authors: CC
authors: Harris
authors: Paul R
authors: PR
authors: Thompson
authors: Lorne J
authors: LJ
authors: Hofseth
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D000076342:Protein-Arginine Deiminases; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000578:Amidines; D056741:Cyclin D; D019927:Cyclin E; D004791:Enzyme Inhibitors; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases