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.
Highlights
Dysregulated protein arginine deiminase (PAD) activity has been proposed to play a role in the onset and progression of numerous human diseases, including cancer [1]
Cl-amidine causes a p53-dependent G1 arrest To explore the functional implications of PAD inhibition, we first asked whether the PAD inhibitor, Cl-amidine, impacts the cell cycle
We have identified that the inhibition of the PADs by our novel small molecule inhibitor (Cl-amidine) suppresses the high colon cancer risk disease, ulcerative colitis, in mice [4]
Summary
Dysregulated protein arginine deiminase (PAD) activity has been proposed to play a role in the onset and progression of numerous human diseases, including cancer [1]. Elevated levels of PAD enzymes and/ or citrullinated proteins are found in multiple chronic conditions, including colitis and colon cancer [1,4,5,6,7]. In this light, we have developed inhibitors of PADs, and one particular inhibitor, called Chlor-amidine (Cl-amidine), has been shown to have cytotoxicity against cancer cell lines [8], and can be used to prevent and treat the high colon cancer risk disease, ulcerative colitis in mice [4]
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