Role of abberant proteolysis in the pathogenesis of APL

ROLE OF UNFOLDED PROTEIN RESPONSE (UPR) AND AUTOPHAGY IN THE REGULATION OF GROWTH AND APOPTOSIS OF APL CELLS NG PING PING ANGELA NATIONAL UNIVERSITY OF SINGAPORE 2009 ROLE OF UNFOLDED PROTEIN RESPONSE (UPR) AND AUTOPHAGY IN THE REGULATION OF GROWTH AND APOPTOSIS OF APL CELLS NG PING PING ANGELA (M.Sc., NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY NUS GRADUATE SCHOOL FOR INTEGRATIVE SCIENCES AND ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2009 i ACKNOWLEDGEMENTS I would like to take this opportunity to express my deepest gratitude to my supervisor, Dr Matiullah Khan, for his guidance, encouragement, and ingenuity throughout the course of this work and for providing me the opportunity to independent research work. He has been the most understanding and patient mentor one could ever ask for. I would also like to extend my gratitude to Prof Yoshiaki Ito for giving me the opportunity to work in the Oncology Research Institute (ORI); without his support, the completion of this thesis would not have been possible. I am also grateful to A/Prof CS Chen for being on my thesis advisory committee, providing me with much invaluable advice. I am also indebted to Ms Selena Gan for her encouragement and help rendered for my application of the A-Star Graduate Scholarship. My appreciation goes to all at the Electron Microscopy Unit (Yong Loo Lin School of Medicine, National University of Singapore): Prof Mary Ng, Micky, Suat Hoon, Lucas and Deborah, who have been exceptionally helpful and generous in sharing their knowledge and experiences. My sincere appreciation also goes to present and ex-members of ORI: Tada san, Tomoko, Tun Kiat, Fen Yi, Peiyi, Baidah, Tiling and Diyanah, for their wonderful friendship and continuous support. It has also been a great pleasure working with my lab-mates: Jek, Hannah, Li Feng, Leo, Azhar, Dawn, Norlizan and Wai Kay. I am grateful and fortunate to have had their assistance and company during the long hours of doing experiments. Special thanks go to my family members for their continuous encouragement and support. I am most grateful to my parents and sisters, Cecily and Pauline, for their care, concern and support. Most importantly, the love, belief and motivation that I have received from my husband, Shao Siong and my daughter, Rhea, during ii this journey are very much appreciated. Their understanding and care allowed me to remain focused on my work. Shao Siong’s encouragement and companionship never cease to cheer me up when things are not working well. Finally, I am grateful for the Graduate Research Scholarship provided by the A-Star Graduate Academy (AGA). I would like to thank the institution for giving me this opportunity to pursue graduate study, because without this chance, none of all these would have been realised. Ng Ping Ping Angela Jan 2009 iii TABLE OF CONTENTS ACKNOWLEDGEMENTS i TABLE OF CONTENTS iii SUMMARY ix LIST OF PUBLICATIONS xi LIST OF TABLES xii LIST OF FIGURES xiii LIST OF ABBREVATIONS xix INTRODUCTION 1.1 Leukemia 1.2 Acute promyelocytic leukemia (APL) 1.2.1 PML-RARα 1.2.2 N-CoR 1.2.3 Current knowledge of PML-RAR/N-CoR and its perceived mechanism in APL 13 1.2.4 Currently available therapeutics for APL 14 1.2.5 Rationale for novel therapeutics for APL 17 ER stress and unfolded protein response 19 1.3.1 Protein folding in the cell 19 1.3.2 The unfolded protein response 21 1.3.3 UPR-induced apoptosis 24 Autophagy 27 1.4.1 Macroautophagy 27 1.4.2 Chaperone mediated autophagy 33 Our hypothesis and objectives 34 1.3 1.4 1.5 iv 1.5.1 Our hypothesis about leukemogenesis in APL by PML-RARα 34 1.5.2 Objectives of the project 35 MATERIALS AND METHODS 37 2.1 Materials 38 2.1.1 Bacterial strains 38 2.1.2 Cell lines 38 2.1.3 Plasmids 39 2.1.4 Reagents, media and buffers 42 2.2 2.1.4.1 Media and reagents for bacterial culture 42 2.1.4.2 Media and reagents for mammalian cell culture 43 2.1.4.3 General buffers preparation 45 Methods 51 2.2.1 Plasmid isolation 51 2.2.2 Maintenance of mammalian cells 52 2.2.3 Cell proliferation assay 52 2.2.4 Trypan blue cell viability test 52 2.2.5 Giemsa-Wright staining 53 2.2.6 Transfection of 293T cells 53 2.2.7 Immunostaining and fluorescence microscopy 54 2.2.8 Protein extraction from mammalian cells using SDS sample buffer 55 2.2.9 SDS-Polyacrylamide gel electrophoresis (SDS-PAGE) 55 2.2.10 Western blotting 56 2.2.11 Stripping and reprobing of membranes 56 v 2.2.12 Protein estimation using Bio-Rad Assay 57 2.2.13 Cell cycle analysis 57 2.2.14 Differentiation assay through flow cytometry 58 2.2.15 Detection of apoptosis through flow cytometry 58 2.2.16 Neutralisation of ER stress through the proteolytic cleavage of N-CoR protein 59 2.2.16.1 Solubility assay for transfected N-CoR in 293T cells 59 2.2.16.2 Solubility assay for endogenous N-CoR in leukemic cells 60 2.2.16.3 In vitro cleavage assay 60 2.2.16.4 Protease inhibitors assay 61 2.2.16.5 Protease purification 61 2.2.16.6 O-sialoglycoprotein endopeptidase digestion assay 62 2.2.16.7 62 AEBSF inhibition assay 2.2.16.8 Immunostaining of leukemic cells with N-CoR antibody 62 2.2.16.9 Immunostaining of transfected 293T cells with N-CoR and GRP78 antibodies 63 2.2.16.10 Knock-down of OSGEP in NB4 cells 63 2.2.17 ER stress and N-CoR loss support cellular growth through autophagy 64 2.2.17.1 Treatment of leukemic cells with Bafilomycin-A1 64 2.2.17.2 Glucose starvation of leukemic cells 65 2.2.17.3 Measurement of internal glucose 65 2.2.17.4 Measurement of internal ATP 65 2.2.17.5 Immunostaining of leukemic cells with Lamp-2 and LC3 antibodies 66 2.2.17.6 Staining of NB4 and HL60 cells with acridine orange 66 vi 2.2.17.7 Induction of ER stress in NB4 cells using known ER stressors 67 2.2.17.8 Western analysis of crude lysates of leukemic cells 67 2.2.17.9 Sample preparation for electron microscopy 67 2.2.17.10 Immuno-gold staining for electron microscopy 69 2.2.17.11 Silencing of N-CoR in NB4 cells 70 2.2.18 Therapeutic targeting of cytoprotective UPR and autophagy with AEBSF 71 2.2.18.1 Treatment of leukemic cells with AEBSF 71 2.2.18.2 Stabilisation of endogenous N-CoR in AEBSF-treated NB4 cells 72 2.2.18.3 Preparation of cytosolic fractions from AEBSF-treated NB4 cells 72 2.2.18.4 Western analysis of crude lysates of AEBSF-treated NB4 cells 73 2.2.19 Therapeutic targeting of cytoprotective UPR and autophagy with curcumin 73 2.2.19.1 Treatment of leukemic cells with curcumin 73 2.2.19.2 Solubility assay for transfected N-CoR in 293T cells after curcumin treatment 73 2.2.19.3 Solubility assay for endogenous N-CoR in NB4 cells after curcumin treatment with DNase treatment 74 2.2.19.4 Analysis of phosphorylated N-CoR after curcumin treatment 74 2.2.19.5 Fluorometric caspase activity test 76 2.2.19.6 Analysis of proteosomal inhibition using the Proteasome Sensor vector 77 2.2.19.7 Fluorometric proteasomal activity assay 77 2.2.19.8 Analysis of ER expansion after curcumin treatment 77 2.2.19.9 Analysis of induction of UPR pathways 78 2.2.19.10 Western Analysis of curcumin-treated cells 79 vii 2.2.19.11 In vitro cleavage assay with crude lysates from curcumin-treated cells 79 RESULTS AND DISCUSSION 80 3.1 Results 81 3.1.1 ER stress is neutralized through the proteolytic cleavage of N-CoR protein 81 3.1.1.1 Misfolded N-CoR is cleaved in APL cells 81 3.1.1.2 N-CoR cleavage is inhibited by protease inhibitors or EDTA 88 3.1.1.3 N-CoR is cleaved by a glycoprotein endopeptidase 88 3.1.2 ER stress and N-CoR loss support cellular growth through autophagy 99 3.1.2.1 Autophagy is activated in APL cells 99 3.1.2.2 Autophagy supports cellular growth in APL 101 3.1.2.3 N-CoR is degraded through cytoprotective autophagy 120 3.1.2.4 Inhibition of autophagy sensitizes APL cells to UPR-induced apoptosis 127 3.1.3 AEBSF therapeutically targets cytoprotective UPR and autophagy 131 3.1.3.1 AEBSF promotes growth arrest of APL cells 131 3.1.3.2 AEBSF sensitises APL to UPR-induced apoptosis 137 3.1.3.3 AESBF inhibits early autophagy in NB4 cells 149 3.1.4 Curcumin therapeutically targets cytoprotective UPR and autophagy 153 3.1.4.1 Curcumin promotes growth arrest, differentiation and cell-cycle arrest of APL cells 153 3.1.4.2 Curcumin induces apoptosis of APL cells 162 3.1.4.3 Curcumin stabilises N-CoR by indirectly inactivating N-CoR cleaving protease(s) 169 viii 3.2 3.1.4.4 Proteasome inhibition by curcumin results in accumulation of N-CoR 175 3.1.4.5 Curcumin sensitises APL cells to UPRinduced apoptosis 181 3.1.4.6 Curcumin inhibits cytoprotective autophagy in APL 187 Discussion 194 3.2.1 ER stress is neutralised through cleavage of misfolded N-CoR protein 194 3.2.2 ER stress and N-CoR loss support cellular growth through autophagy 199 3.2.3 AEBSF therapeutically targets cytoprotective UPR and autophagy 204 3.2.4 Curcumin 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[...]... agents that induced growth arrest in APL cells, possibly by blocking the degradation of N-CoR protein AEBSF, a selective serine protease inhibitor, sensitises APL cells to UPR-induced apoptosis by inducing accumulation of misfolded N-CoR protein in the ER Curcumin, on the other hand, promoted both differentiation and apoptosis of APL cells, possibly by blocking proteasome-mediated and protease-induced... survival of tumour cells in diffuse large B-cell lymphomas (58) N-CoR is also implicated in neuronal diseases and cancers In Huntington’s disease, a co-localization of N-CoR and mSin3 is observed in the cytoplasm of the cortical and caudate cells, whereas in cells of healthy brains, they are found in both the cytoplasm and nucleus This suggests a role of N-CoR delocalisation in the pathogenesis of Huntington’s... protein found in 95% cases of APL (17, 18) In the remaining 5% cases of APL, fusions of RARα to other genes such as the promyelocytic leukemia zinc finger (PLZF) (19), neucleophosmin (NPM) (20), nuclear mitotic apparatus (NuMA) (21) and signal transducer and activator of transcription 5b (STAT5b) (22) Structure and effects of PML-RARα in APL will be further discussed in Section 1.2.1 and 1.2.3 The PLZFRARα... protein contains the entire N-terminal transcriptional effector region of PLZF (including the POZ/BTB domain) as well as the first two zinc fingers of the protein fused to RARα As in the case of PML-RARα, PLZF-RARα can bind as homodimers to RA response elements (RAREs) and repress transcription PLZFRARα–associated APL is relatively resistant to ATRA because PLZF-RARα binds much more strongly to the. .. HDAC complex by binding at the CoR sites on both PML and the POZ/BTB domain on PLZF (19) In the third class of fusion protein, NPM-RARα is formed as a result of chromosomal translocation between chromosome 5 and 17 It has the 5’ end of nucleophosmin joined with the 3’ end of RARα NPM-RARα acts as transcriptional activators of retinoic acid- 4 Table 1.1 Summary of some of the features of chronic leukemia... disruption of the retinoic acid signalling pathway (21) In the last class of translocation, fusion occurs between STAT5b and RARα This fusion results in delocalisation of Stat5b from the cytoplasm to the nucleus Leukemogenesis in this case is thought to be due to the dysregulation of the JAK/STAT signalling pathways (22) 1.2.1 PML-RARα PML-RAR fusion protein contains the N-terminus of PML fused to the DNA... protein is also found in autophagosomes of NB4 cells with anti-N-CoR antibody by immuno-gold staining As expected, BA-1-induced inhibition of autophagy decreases the viability of APL cells and reduces their intracellular glucose and ATP levels Moreover, APL cells continue to grow and maintain their intracellular glucose and ATP levels even under glucose-starved conditions BA-1-induced inhibition of autophagy... is a malignant disorder of the blood-forming cells of the bone marrow It is characterised by the clonal expansion of hematopoietic cells, due to genetic alterations in cells of the hematopoietic lineages It is categorised as chronic or acute and lymphoid or myeloid leukemia based on the maturity and the lineage of the main population of cancer cells present The four main types of leukemia are: acute... non -APL cells, while in APL cells, this apoptotic response is neutralised through the processing of misfolded N-CoR protein by OSGEP, a glycoprotein endopeptidase selectively activated in APL cells Down-regulation of OSGEP in NB4 cells by shRNA led to the stabilisation of full-length N-CoR and induced apoptosis of NB4 cells The obvious link of N-CoR degradation with the survival of APL cells also suggests... RXR and inactivation of these proteins, and homodimerisation of the fusion protein and binding to PML or RARα target genes (29 ) Reprinted by permission from The Publishing Division of the Massachusetts Medical Society: [New England Journal of Medicine] Copyright ©[1993]Massachusetts Medical Society All rights reserved 7 thirds of APL patients (28) The detection of specific fusion transcripts of PMLRARα . sensitises APL cells to UPR-induced apoptosis by inducing accumulation of misfolded N-CoR protein in the ER. Curcumin, on the other hand, promoted both differentiation and apoptosis of APL cells,. 3.82. Curcumin inhibits the degradation of the proteosome 179 sensor in HEK293T cells in a dose-dependent manner. Figure 3.83. Curcumin inhibits the degradation of the N-CoR-GFP in 180 HEK293T. ROLE OF UNFOLDED PROTEIN RESPONSE (UPR) AND AUTOPHAGY IN THE REGULATION OF GROWTH AND APOPTOSIS OF APL CELLS NG PING PING ANGELA NATIONAL UNIVERSITY OF SINGAPORE