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Anti-Oxidant Pathogenesis of High-Grade Glioma DISSERTATION

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Anti-Oxidant Pathogenesis of High-Grade Glioma DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Ji Eun Song, M.S. Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2015 Dissertation Committee: Dr. Chang-Hyuk Kwon, Advisor Dr. Balveen Kaur, Co-advisor Dr. Vincenzo Coppola Dr. Thomas Ludwig Copyright by Ji Eun Song 2015 Abstract High-grade glioma (HGG) is the most aggressive primary brain malignancies, and is incurable despite the best combination of current cancer therapies. A median patient survival of glioblastoma (GBM, the most aggressive grade 4 glioma) is only 14.6 months (Stupp et al., 2005). Therefore, innovative and more effective therapy for HGG is urgently needed. It has been known that dysregulated reactive oxygen species (ROS) signaling is associated with many human diseases, including cancers. Oxidative stress by excessive accumulation of ROS has been known to promote carcinogenesis through both genetic and epigenetic modifications (Ziech, Franco, Pappa, & Panayiotidis, 2011). Expressions of anti-oxidant proteins are reportedly increased by ROS- induced oxidative stress (Polytarchou, Pfau, Hatziapostolou, & Tsichlis, 2008). Because excessive oxidative stress can cause cellular senescence and apoptosis, it appears that tumor cells overexpress anti-oxidant proteins as a defense mechanism against elevated ROS. Therefore, targeting a predominant anti-oxidant protein could be an effective strategy for treating tumors. Peroxiredoxin 4 (PRDX4) is an ROS-scavenging enzyme and facilitates proper protein folding in the endoplasmic reticulum (ER). We reported that PRDX4 levels ii were highly increased in a majority of human HGGs as well as in a mouse model of HGG. Knockdown of PRDX4 expression significantly decreased HGG cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In an orthotopic transplantation model, Prdx4 knockdown suppressed HGG infiltration and significantly prolonged mouse survival. These data suggest that PRDX4can be a novel target for HGG therapies in the future. Piperlongumine is a natural compound that kills multiple cancer types with elevation of intracellular levels of ROS. Importantly, piperlongumine selectively kills cancer cells with little effect on normal counterpart cells. Although these findings suggest that piperlongumine could be useful for treating cancers, the mechanism by which the drug selectively kills cancer cells remains unknown. The piperlongumine treatment increased ROS levels and preferentially killed HGG cells with little effect in normal brain cells. We also found that HGG cells expressed higher levels of the putative piperlongumine targets than did normal neural stem cells (NSCs). Furthermore, piperlongumine treatment increased oxidative inactivation of PRDX4 in HGG cells, but not in normal NSCs. Moreover, piperlongumine exacerbated intracellular ER stress, an effect that was mimicked by suppressing PRDX4 expression. Our results revealed that the mechanism by which piperlongumine preferentially kills HGG cells involves PRDX4 inactivation, thereby inducing ER stress. Therefore, piperlongumine treatment could be considered as a novel therapeutic option for HGG treatment. iii Current standard chemotherapy for HGG is temozolomide (TMZ) (Stupp et al., 2005). However, the efficacy of TMZ is only beneficial to half of patients because of TMZ resistance. Several recent reports suggest that suppression of ROS by anti- oxidant protein expression and STAT3 activation contributes to TMZ resistance (E. S. Lee, Ko, Joe, Kang, & Hong, 2011; Oliva, Moellering, Gillespie, & Griguer, 2011; W. B. Zhang et al., 2010). In this study, we found that combination treatment of piperlongumine and TMZ effectively kills two different TMZ resistant human HGG cell lines. The mechanism of synergistic effect of combination treatment is not clear, and in vivo studies need to be done before applying it to patient. However, combination treatment of the drugs could be a new strategy for treating HGG. iv Dedication To all my family members All I have and will accomplish are only possible due to their love and sacrifices v Acknowledgments First and foremost, I would like to thank my advisor, Dr. Chang-Hyuk Kwon for his guidance, encouragement, and patience. I could not have achieved my goals for this dissertation without his support. I would like to express my gratitude to my co-advisor Dr. Balveen Kaur for her support in last years of my work as a graduate student at OSU. I am also grateful to my committee members Drs. Coppola and Ludwig for their supervision throughout this process. I would like to thank Dr. Tae Hyong Kim. I have enjoyed working with him at Kwon lab for 5 years. I also would like to thank all Kaur lab members for their help during last semester. I would like to express the appreciation to all co-authors of my publications for their help to publish my works. I could not complete my works without their help. In addition, I would like to thank Dr. David Bisaro at Molecular, Cellular and Developmental Biology program for being supportive during my graduate study at The Ohio State University. vi Vita 2000 - 2004……………………………………B.S. Life Science, Hanyang University, Seoul, South Korea 2005 - 2007……………………………………M.S. Life Science, Hanyang University, Seoul, South Korea 2009– present………………………………..Graduate Research Associate, MCDB program, Department of Neurological Surgery, The Ohio State University Publications 1. Song J, Park S, Kim M and Shin I. (2008) Down-regulation of Notch- dependent transcription by Akt in vitro. FEBS Lett. 582(12):1693-9. 2. Park S, Song J, Joe CO and Shin I. (2008) Akt stabilizes estrogen receptor alpha with the concomitant reduction in its transcriptional activity. Cell Signal. 20(7):1368-74. vii 3. Kim M, Ju JH, Jang K, Oh S, Song J, Kim CG and Shin I. (2012) Protein kinase Cδ negatively regulates Notch1-dependent transcription via a kinase- independent mechanism in vitro. Biochim Biophys Acta. 1823(2):387-97. 4. Kim TH, Song J, AlcantaraLlaguno SR, Murnan E, Liyanarachchi S, Palanichamy K, Yi JY, Viapiano MS, Nakano I, Yoon SO, Wu H, Parada LF and Kwon CH. (2012) Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth. PLoS One. 7(8):e42818. 5. Price RL, Song J, Bingmer K, Kim TH, Yi JY, Nowicki MO, Mo X, Hollon T, Murnan E, Alvarez-Breckenridge C, Fernandez S, Kaur B, Rivera A, Oglesbee M, Cook C, Chiocca EA and Kwon CH. (2013) Cytomegalovirus contributes to glioblastoma in the context of tumor suppressor mutations. Cancer Res. 73(11):3441-50. 6. Kim TH†, Song J†, Kim SH, Parikh AK, Mo X, Palanichamy K, Kaur B, Yu J, Yoon SO, Nakano I and Kwon CH. (2014) Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells. Neuro-Oncol 16(10):1354-64. Equal contribution†. viii Fields of Study Major Fields: Molecular, Cellular and Developmental Biology Neuro-oncology ix Table of Contents Abstract .............................................................................................................................. ii Dedication .......................................................................................................................... v Acknowledgments ............................................................................................................ vi Vita .................................................................................................................................... vii Table of Contents ............................................................................................................... x List of Tables .................................................................................................................... xv List of Figures ................................................................................................................. xvi List of Abbreviations ...................................................................................................... xix Chapter 1. Introduction ................................................................................................. 1 1.1. High-grade gliomas ............................................................................................... 1 1.2. Reactive oxygen species (ROS) in cancer ............................................................. 2 1.3. Tumor drivers ........................................................................................................ 3 1.4. Peroxiredoxin 4 (PRDX4) ..................................................................................... 4 1.5. Endoplasmic reticulum (ER) stress ....................................................................... 6 1.6. Research aims and tools ........................................................................................ 6 x Chapter 2. Suppression of PRDX4 in GBM Cells Increases Apoptosis and Reduces Tumor Growth .................................................................................................................. 12 2.1. Introduction ......................................................................................................... 12 2.2. Materials and methods ......................................................................................... 14 2.2.1. Mice .............................................................................................................
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