Identification Of Cdk1 As An Aspirin And Salicylic Acid Binding Protein: A Potential Role In Chemoprevention

Data emerging from the past 10 years have consolidated the rationale for investigating the use of aspirin for chemoprevention; however, the mechanisms leading to its anti-cancer effects are still being elucidated. We hypothesized that aspirin’s ability to exert chemopreventive effects may involve altering the levels and activity of cell cycle regulatory proteins. In the present study, using HT-29 colon cancer cells and other cancer cells, we demonstrated that both aspirin and its primary metabolite, salicylic acid, downregulated the protein and mRNA levels of cyclin B1 and cyclin dependent kinase-1 (CDK1). Lactacystin, a 26S proteosomal inhibitor, prevented aspirin and salicylic acid mediated degradation of cyclin B1, but not CDK1. Decrease in protein levels of cyclin B1/CDK1 was correlated with a corresponding decrease in CDK1 kinase activity. Molecular docking studies showed that aspirin and salicylic acid independently can dock on CDK1 through interactions with Leucine 83. Incubation of recombinant CDK1 with aspirin resulted in acetylation at lysine residues, this was also observed in cell culture experiments. Pre-incubation of CDK1 with salicylic acid dose dependently prevented aspirin’s ability to acetylate CDK1 in purified preparations confirming the data obtained from molecular docking studies. Our results show that CDK1 is a salicylic acid binding protein (SABP) and the chemopreventive actions of aspirin may involve modulation of levels and activity of cyclin B1 and CDK1. Citation Format: Jayarama B. Gunaje, D.Ramesh Kumar, Siddharth Kesharwani, Eduardo Callegari, Hemachand Tummala, Rakesh Dachineni. Identification of CDK1 as an aspirin and salicylic acid binding protein: a potential role in chemoprevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2354. doi:10.1158/1538-7445.AM2017-2354