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Sphingosine Kinase 1 Inhibitor, a Novel Inducer of Autophagy

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Sphingosine Kinase 1 Inhibitor, a Novel Inducer of Autophagy Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2009 Sphingosine Kinase 1 Inhibitor, A Novel Inducer of Autophagy Daniel Meza Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Biochemistry, Biophysics, and Structural Biology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/1871 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Daniel Meza 2009 All Rights Reserved SPHINGOSINE KINASE 1 INHIBITOR, A NOVEL INDUCER OF AUTOPHAGY A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by DANIEL MEZA Director: SARAH SPIEGEL PROFESSOR AND CHAIR, BIOCHEMISTRY AND MOLECULAR BIOLOGY Virginia Commonwealth University Richmond, Virginia August 2009 Acknowledgement Many thanks to Dr. Spiegel who acted as my mentor and guide, Dr. Fang and Dr. Hylemon who were members of my committee, Dr. Lépine who took me under her scientific wing and supported me in all aspects of this project, Dr. Takabe and Dr. Hoon whose insights prepared me for the future, and Dr. Kapitonov whose love of research, technical advice and willingness to discuss even the most far-fetched of ideas, buoyed me along. Also, many thanks to my family (Mark, Paula and Benjamin) and friends (especially, Dan, Jochen, Mona and Dmitry) who gave this project its human element. We stand upon the shoulders of those who came before us. Thanks for all the shoulders. i Table of Contents Page Acknowledgements ............................................................................................................. ii List of Figures ............................................................................................................... iii, iii List of Abbreviations ......................................................................................... iii, iii, iii, iii Abstract…….. ............................................................................................................ xii, xiii Chapter 1 Introduction ........................................................................................................ 14 Autophagy .................................................................................................. 14 Roles of Macroautophagy ........................................................................... 14 Autophagosome Formation and Maturation ............................................... 17 Autophagosome Maturation ....................................................................... 17 Atg5 ............................................................................................................ 18 LC3 ............................................................................................................. 20 Beclin .......................................................................................................... 21 Signaling Mediators of Autophagy ............................................................. 23 mTOR ......................................................................................................... 24 Endoplasmic Reticulum .............................................................................. 25 Sphingosine-1- Phosphate (S1P) ................................................................ 29 SphK2 ......................................................................................................... 32 SphK1 ......................................................................................................... 33 Sphingolipid Metabolism and Autophagy .................................................. 34 iii SK1-I ........................................................................................................ 35 Statement of Intent ...................................................................................... 37 2 Materials and Methods .............................................................................. 38 Materials ..................................................................................................... 38 Cells ............................................................................................................ 38 Cell Transfection ........................................................................................ 38 RNA interference ........................................................................................ 39 Confocal Microscopy ................................................................................. 39 Western blot analysis .................................................................................. 40 Cell Death Assay ........................................................................................ 41 Statistical Analysis ..................................................................................... 41 3 Results ............................................................................................................. 42 SK1-I Induces autophagy in a time and dose dependent manner…............42 SK1-I does not trigger classical Beclin 1 or mTORC1 signaling…….…...44 Non-canonical mTORC2 signaling is observed…………………………...45 Akt is not involved in autophagy…………………………………………..46 SK1-I induced ER stress……………………………………………………46 Atg5 is necessary for SK1-I autophagic induction…………………………47 SK1-I induces non-apoptotic cell death in wild type HCT116 cells and apoptosis in p53 nullcells…………………………………………………..48 4 Discussion ....................................................................................................... 62 iv Autophagy Induction by SK1-I: an Unexpected Result .............................. 62 Absence of Beclin1 or mTORC1 effects offer mechanistic insights…….....65 Translational effects, cytoskeletal changes, and a role for the ER………..67 Autophagic Death? Need for Further Investigation of the Mechanisms of Death ……………………………………………………………………...68 Literature Cited ................................................................................................................. 71 Vita .................................................................................................................................... 97 v List of Figures Page Figure 1: Atg5 and LC3II contribute to early formation of the autophagosome .............. 19 Figure 2: ER stress pathways implicated in autophagy .................................................... 27 Figure 3: Sphingolipid Synthesis ...................................................................................... 31 Figure 4: Structure of SK1-I ............................................................................................. 36 Figure 5: SK1-I Induces autophagy with different intensity in human wild type p53 expressing HCT116 colon carcinoma cells, and in their p53-null counterparts . .......................................................................................................................................... 50 Figure 6: SK1-I induces LC3 lipidation in HCT116 cells ........................................................................................................................................... 51 Figure 7: SK1-I induces autophagy without increasing Beclin1 ........................................................................................................................................... 52 Figure 8: Atg5 but not Beclin1 is required for SK1-I-induced autophagosome formation ........................................................................................................................................... 53 Figure 9: SK1-I does not inactivate mTOR complex 1 ........................................................................................................................................... 54 Figure 10: SK1-I treatment decreased phosphorylation of Akt concomitantly with LC3 lipidation ........................................................................................................................................... 55 Figure 11: SK1-I induces autophagy independently of Akt and mTORC1 ........................................................................................................................................... 56 Figure 12: SK1-I treatment induces ER stress ........................................................................................................................................... 57 Figure 13: SK1-I induces non-autophagic death in wild type HCT116 cells and apoptosis in p53-/- HCT116 cells ...................................................................................................................................... 58,59 Figure 14: SK1-I did not induce PARP cleavage in wt cells vi ........................................................................................................................................... 60 Figure 15: SK1-I decreases ERK1/2 phosphorylation ........................................................................................................................................... 61 Figure 16: Schema of Autophagy induced by SK1-I ........................................................................................................................................... 70 vii List of Abbreviations
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