Elucidating the molecular mechanism of ATP synthase inhibitor citreoviridin on anti-proliferative activity of breast cancer cells

• Main Authors: Nai-Ning Chen, 陳乃寧
• Other Authors: Hsueh-Fen Juan
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/71051473606600653226

碩士 === 國立臺灣大學 === 分子與細胞生物學研究所 === 100 === ATP synthase presents in all organisms and usually located on the membrane of mitochondria of eukaryotic cells. Our previous study showed that ATP synthase was upregulated in breast cancer tissues and could be expressed on tumor cell surface more than on normal cell surface (Journal of Proteome Research, 2008). Here, we found that citreoviridin displayed significant anti-proliferative activity in MCF-7 cells, which may be attributed to its induction of cell cycle arrest. To further elucidate the mechanism of citreoviridin, we performed a proteomic study combining two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. By comparing citreoviridin-treated and control proteome profiles of MCF-7 cells, we found the major function of these differential expressed proteins was related to protein folding. Accumulation of unfolded proteins in the lumen of the ER could activate the unfolding protein response (UPR), which could induce cell cycle arrest at G0/G1 phase. We demonstrated that citreoviridin could induce cell cycle arrest at G0/G1 phase through triggering of UPR, the phosphorylation of eIF2α and induction of translational inhibition, thereby blocking general protein synthesis including the cell cycle regulator cyclin D1 and retinoblastoma protein. Our results showed that ATP synthase inhibitor citreoviridin could be a potential drug for breast cancer therapy.