【電機系書報討論演講訊息】

書報討論網頁：http://lms.nthu.edu.tw/course/19186

演講公告網址：/p/403-1175-2629-1.php

題   目：Dynamic Response Network of Ectopic ATP Synthase Blockade

講   員：阮雪芬 教授 (台灣大學分子與細胞生物學研究所)

時         間：2014年12月12日(星期五) 下午2時20分

地         點：學習資源中心旺宏館245教室(圖書館2樓)

Abstract:

Ectopic expression of F1Fo-ATP synthase on the plasma membrane has previously been described in several different cancer cell types and may serve as a tumor marker, but its role remains unclear. In this study, we demonstrate the presence of ectopic ATP synthase on the plasma membrane of lung adenocarcinoma cells. Using homology modeling and docking simulation, we successfully discover the ATP synthase inhibitor citreoviridin. Moreover, we found that ATP synthase inhibitor citreoviridin can induce cell cycle arrest and inhibit the proliferation and anchorage-independent growth of lung cancer cells. We performed temporal proteomics and phosphoproteomics to elucidate the dynamic changes of ecto-ATP synthase blockade in cells and xenograft model. Based on the protein expression profiles and mathematical modeling, we propose a response network implying citreoviridin induces an unfolded protein response (UPR) with phosphorylation of a protein synthesis regulator, eukaryotic translation initiation factor 2α (eIF2α) leading to inhibition on cell growth. Furthermore, citreoviridin-enhanced eIF2α phosphorylation could be reversed by knockdown of PKR-like ER kinase (PERK) and antioxidant N-acetylcysteine, indicating reactive oxygen species (ROS) boost UPR under citreoviridin treatment. Elevation of UPR and ROS generates a positive feedback loop and inhibits cell proliferation in a convergent way. These findings reveal the molecular role and the therapeutic potential of inhibiting ectopic ATP synthase in targeting lung cancer cells.

講者介紹：

Hsueh-Fen Juan received her BS and MS degree in Botany and PhD in Biochemical Sciences from National Taiwan University (NTU) in 1999. She worked as a research scientist in the Japan International Research Center for Agricultural Sciences (Tsukuba, Japan) during 2000-2001 and a postdoctoral research fellow in the Institute of Biological Chemistry, Academia Sinica (Taipei, Taiwan) during 2001-2002.

She started her academic career in the Department of Chemical Engineering, National Taipei University of Technology as an assistant professor and in the Department of Computer Science and Information Engineering at NTU as an adjunct assistant professor in 2002. She moved to NTU in 2004 as an assistant professor in the Department of Life Science and the Institute of Molecular and Cellular Biology. She was promoted to be an associate professor in 2006 and full professor in 2009 in the Department of Life Science, Institute of Molecular and Cellular Biology and Graduate Institute of Biomedical Electronics and Bioinformatics, NTU. Dr. Juan is currently working on systems biology by integrating transcriptomics, proteomics and bioinformatics for biomarker and drug discovery.

Prof. Juan has developed a number of novel methods to advance systems-biology research and applied such approach for drug discovery and elucidating molecular mechanism of drug responses in cancer cells. She has published more than 80 journal papers and edited a scientific book entitled as Systems Biology: Applications in cancer-related research (2012). She is now the editor of Computational and Mathematical Methods in Medicine (Hindawi Publishing Corporation), PeerJ and Stem Cell Treatments (Publisher Frontiers, joining Nature Publishing Group). She also serves as the reviewer of 41 various journals such as Drug Discovery Today (Elsevier), Molecular and Cellular Proteomics (ASBMB), Journal of Proteome Research (ACS), Proteomics (Wiley-VCH), Bioinformatics (Oxford) and BMC Systems Biology (Springer). To promote systems biology field, she has organized several international systems biology and bioinformatics symposiums. She is one of the founders of Center for Systems Biology (NTU), and currently the Council Member of three societies, the Taiwan Society for Biochemistry and Molecular Biology, Taiwan Proteomics Society, and Taiwan Bioinformatics and Systems Biology Society. Since Dr. Juan made significant contributions through systems biology approach to development of methodology and cancer therapy; she received the awards “Taiwan's Ten Outstanding Young Persons” (十大傑出青年) (2008), FY2011 JSPS Invitation Fellowship Program for Research in Japan (2011), K. T. Li Breakthrough Award (李國鼎穿石獎) by Institute of Information and Computing Machinery (2012), and National Science Council (NSC)/Ministry of Science and Technology (MOST) Award for Special Talents of the Colleges (2010-2015).

Dynamic Response Network of Ectopic ATP Synthase Blockade

Ectopic expression of F1Fo-ATP synthase on the plasma membrane has previously been described in several different cancer cell types and may serve as a tumor marker, but its role remains unclear. In this study, we demonstrate the presence of ectopic ATP synthase on the plasma membrane of lung adenocarcinoma cells. Using homology modeling and docking simulation, we successfully discover the ATP synthase inhibitor citreoviridin. Moreover, we found that ATP synthase inhibitor citreoviridin can induce cell cycle arrest and inhibit the proliferation and anchorage-independent growth of lung cancer cells. We performed temporal proteomics and phosphoproteomics to elucidate the dynamic changes of ecto-ATP synthase blockade in cells and xenograft model. Based on the protein expression profiles and mathematical modeling, we propose a response network implying citreoviridin induces an unfolded protein response (UPR) with phosphorylation of a protein synthesis regulator, eukaryotic translation initiation factor 2α (eIF2α) leading to inhibition on cell growth. Furthermore, citreoviridin-enhanced eIF2α phosphorylation could be reversed by knockdown of PKR-like ER kinase (PERK) and antioxidant N-acetylcysteine, indicating reactive oxygen species (ROS) boost UPR under citreoviridin treatment. Elevation of UPR and ROS generates a positive feedback loop and inhibits cell proliferation in a convergent way. These findings reveal the molecular role and the therapeutic potential of inhibiting ectopic ATP synthase in targeting lung cancer cells.

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