Location: Diet, Genomics and Immunology LaboratoryTitle: Javamide-I-O-methyl ester increases p53 acetylation and induces cell death via activating caspase 3/7 in monocytic THP-1 cells
Submitted to: Phytomedicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/5/2016
Publication Date: 12/1/2016
Citation: Park, J.B. 2016. Javamide-I-O-methyl ester increases p53 acetylation and induces cell death via activating caspase 3/7 in monocytic THP-1 cells. Phytomedicine. 23(13):1647-1652. doi: 10.1016/j.phymed.2016.10.004.
Interpretive Summary: The sirtuins are proteins able to deacetylate internal lysine residues that are acetylated on the e-amino group of lysine. This reversible post-translational modification of acetylation quickly manipulates a protein’s activity and regulates processes as diverse as metabolic flux and DNA repair. Therefore, they have been considered as a good target molecule for several human diseases including diabetes, cardiovascular and neurodegenerative diseases and cancer. Particularly, sirtuin2 is believed to be involved in pathological processes of neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. Therefore, in this paper, potential effects of javamide-I found in coffee on sirtuin2 and its effects on the acetylation levels of histone H3, alpha-tubulin, and p53 were investigated. Javamide-I was able to inhibit sirtuin2 strongly, and exhibited noncompetitive inhibition of sirtuin2 with Ki = 9.6 'M. Javamide-I was also able to increase the acetylation of histone H3, alpha-tubulin, and p53 in monocytic THP-1 cells. This study provides new information about sirtuin2-inhibiting activity of javamide-I found in coffee, which could be utilized in sirtuin-associated human diseases.
Technical Abstract: Our previous study suggested that javamide-II found in coffee could inhibit sirtuin1/2, thereby potentially beneficial in some human diseases such as neuronal degenerative diseases and cancer. In fact, coffee is reported to contain javamide-I, in addition to javamide-II. However, potential effects of javamide-I on sirtuin inhibition are still unknown. Therefore, in this paper, potential effects of javamide-I on sirtuin1 (nuclear), sirtuin2 (cytoplasm) and sirtuin3 (mitochondria) were investigated, and its effects on the acetylation levels of histone H3, alpha-tubulin, and p53 were also determined. For this study, javamide-I was chemically synthesized and the chemical structure was confirmed using NMR spectroscopic methods. Javamide-I was able to inhibit sirtuin1 (IC50 of 36 uM), and sirtuin2 (IC50 of 6.2 uM). However, the amide had little effect on sirtuin3. Especially related to sirtuin2, the amide exhibited noncompetitive inhibition of sirtuin2 with Ki = 9.6 uM. In supporting the inhibition, a docking simulation showed stronger binding pose of javamide-I to sirtuin2 than EX527. In monocytic THP-1 cells, javamide-I was also able to increase the acetylation of histone H3, alpha-tubulin, and p53. This study suggests that javamide-I found in coffee is likely to inhibit sirtuin2 most, and sirtuin1 in a less degree, thereby providing potentially effects on sirtuin-associated human diseases.