The tricarboxylic acid (TCA) cycle functions as both an oxidative hub to oxidize acetyl-CoA and a biosynthetic hub for the synthesis of nucleotides, amino acids and fatty acids. Glutaminloysis and pyruvate carboxylation are important anaplerotic reactions which maintain TCA cycle integrity by replenishing its intermediates upon the removal for the biosynthesis of biomolecules. Previous studies by our group showed that PC expression is overexpressed in breast cancer tissue patients, and suppression of PC expression in highly metastatic breast cell line, MDA-MB-231, impairs biosynthesis of amino acids, nucleotides and fatty acids from TCA cycle activity, resulting in growth inhibition. Professor Jitrapakdee’s research team found that PC knockdown MDA-MB-231 cells had a low percentage of cell viability in association with accumulation of abnormal cells with large or multi-nuclei. Flow cytometric analysis of annexin V-7-AAD positive cells showed that depletion of PC expression triggers apoptosis with the highest rate at day 4. Cell cycle analysis showed that the apoptotic cell death was associated with G2/M arrest, in parallel with marked reduction of cyclin B levels. Proteomic analysis identifies candidate proteins responsible for the PC-mediated cell cycle arrest and apoptosis in breast cancer cells. These results highlight the possibility of the use of PC as an anti-cancer drug target.
Rattanapornsompong K, Khattiya J, Phannasil P, Phaonakrop N, Roytrakul S, Jitrapakdee S, Akekawatchai C. Impaired G2/M cell cycle arrest induces apoptosis in pyruvate carboxylase knockdown MDA-MB-231 cells. Biochem Biophys Rep. 2021 Jan 12;25:100903. doi: 10.1016/j.bbrep.2020.100903.
|Prof. Sarawut Jitrapakdee