Regulation of Growth Factor Signaling by Vitamin D in Human Prostate Cancer Cells

..................................................................................................................7 ABBREVIATIONS ........................................................................................................8 LIST OF ORIGINAL COMMUNICATIONS ...............................................................10 INTRODUCTION ........................................................................................................11 REVIEW OF THE LITERATURE ...............................................................................12 1. DISCOVERY AND CHEMISTRY OF VITAMIN D............................................12 2. METABOLISM AND TRANSPORT OF VITAMIN D ........................................13 3. MOLECULAR MECHANISMS OF VITAMIN D ACTION ................................15 3.1. Regulation of gene expression ........................................................................15 3.1.1. VDR ........................................................................................................15 3.1.1.1. Structure ...........................................................................................15 3.1.1.2. Heterodimerization and nuclear translocation ....................................17 3.1.2. VDRE......................................................................................................18 3.1.3. Cofactors .................................................................................................19 3.2. Rapid nongenomic action ...............................................................................20 4. OVERVIEW OF THE BIOLOGICAL FUNCTIONS OF VITAMIN D.................20 5. PROSTATE AS A VITAMIN D TARGET ORGAN.............................................21 5.1. Historical perspective. Epidemiological studies ..............................................21 5.2. Intraprostatic vitamin D metabolism ...............................................................22 5.3. VDR gene expression in the prostate ..............................................................23 5.4. Action of vitamin D metabolites in prostate cancer cells .................................23 5.4.1. Antiproliferative ......................................................................................23 5.4.2. Prodifferentiative .....................................................................................24 5.4.3. Proapoptotic.............................................................................................24 5.4.4. Antiangiogenic and antiinvasive ..............................................................24 5.5. Crosstalk between vitamin D and androgens ...................................................25 5.6. Clinical trials ..................................................................................................26 6. TRANSFORMING GROWTH FACTORSUPERFAMILY IN PROSTATE CANCER. REGULATION BY VITAMIN D............................................................27 6.1. TGFsuperfamily growth factors in normal and malignant prostate. Prostate-derived factor...........................................................................................27 6.2. TGFfamily growth factor signaling pathway...............................................29 6.2.1. Activation and receptors ..........................................................................29 6.2.2. SMADs....................................................................................................31 6.2.3. SMAD-independent pathways..................................................................32 6.3. Regulation of TGFsignaling by vitamin D ..................................................33 7. PLATELET-DERIVED GROWTH FACTOR SUPERFAMILY IN PROSTATE CANCER. .................................................................................................................35 7.1. PDGF superfamily growth factors in normal and malignant prostate...............35 7.2. PDGF superfamily growth factors signaling pathway .....................................37 7.2.1. Activation and receptors. PDGFR ..........................................................37 7.2.2. Downstream effectors ..............................................................................37 7.2.3. Interaction between PDGFRs and other tyrosine kinase receptor signaling pathways ............................................................................................38 AIMS OF THE STUDY................................................................................................39 MATERIALS AND METHODS...................................................................................40 1. REAGENTS (I, II, III, IV).....................................................................................40 2. CELLS..................................................................................................................40 2.1. Cell culture (I, II, III, IV)................................................................................40 2.2. Treatment with hormones and growth factors (I, II, III, IV) ............................40