Regulation of apoptosis during treatment and resistance development in tumour cells

............................................................................1 ABBREVIATIONS .................................................................2 PAPERS IN THIS THESIS....................................................3 INTRODUCTION...................................................................5 CELL DEATH............................................................................................... 5 Apoptosis .................................................................................................... 5 Caspases .........................................................................................................................6 Apoptosis signalling pathways......................................................................................7 Extrinsic apoptosis .....................................................................................................7 Intrinsic apoptosis. ...................................................................................................10 Cross-talk between the extrinsic and intrinsic pathways ..........................................11 Regulation of apoptosis signalling..............................................................................12 cFLIP .......................................................................................................................12 The Bcl-2 family ......................................................................................................13 IAPs .........................................................................................................................15 NF-κB ......................................................................................................................16 p53 ...........................................................................................................................16 Survival signalling pathways....................................................................................17 Non-classical apoptotic cell death........................................................... 20 Necrosis ........................................................................................................................20 Autophagy ....................................................................................................................21 Mitotic catastrophe......................................................................................................21 CARCINOGENESIS .................................................................................. 23 Treatment modalities ............................................................................... 23 Chemotherapy .............................................................................................................23 Radiotherapy ...............................................................................................................24 Radioimmunotherapy .................................................................................................24 Apoptosis resistance in malignant disease .............................................. 24 Resistance mechanisms ...............................................................................................25 Apoptosis resistance in tumour development and survival ......................................26 Defects in apoptosis signalling supports enhanced proliferation..............................26 Escape of immune surveillance through apoptosis resistance ..................................27 Apoptosis resistance confers insensitivity to cancer therapy....................................27 INTERFERON............................................................................................ 29 Production of type I IFNs........................................................................ 29 The IFN-signalling cascade .................................................................... 30 IFNs as apoptosis inducers ..................................................................... 32 IFN in clinical treatment......................................................................... 33 AIMS OF THIS THESIS......................................................34 RESULTS AND DISCUSSION ...........................................35 APOPTOSIS RESISTANCE IN TUMOURS ........................................... 35 Impaired death receptor signalling in tumour progression ................... 35 Reduced Fas expression in apoptosis resistance........................................................38 Increased cFLIP expression in Fas resistance...........................................................40 General aspects of Fas resistance ...............................................................................41 Impaired IFN-α signalling in tumour progression ................................ 42 Increased cFLIP expression in IFN resistance ..........................................................44 IFN induced cell growth inhibition versus apoptosis................................................45 General aspects of acquired resistance in U937 cells............................. 46 CELL DEATH BY LOW DOSE IRRADIATION.................................... 47 CONCLUDING REMARKS................................................49 ACKNOWLEDGEMENTS..................................................50 REFERENCES ......................................................................53