chapter  11
42 Pages

Regulation of Signaling Pathways by Selenium in Cancer

Kidney Cells ............................................................................. 292 11.7.3 Protein Kinase C ...................................................................... 292

11.8 Effects of Selenium on p53, NF-κB, and AP-1 Nuclear Transcription Factors ............................................................................. 293 11.8.1 p53 Tumor Suppressor ............................................................. 293

11.8.1.1 Redox Regulation of p53 Transcriptional Activity and DNA Repair by Selenium ............... 293

11.8.1.2 p53 Phosphorylation and Apoptosis .................... 294 11.8.2 NF-κB .................................................................................. 295 11.8.3 Activating Protein-1 Family ................................................. 296 11.8.4 Differential Effects on Liver AP-1 and NF-κB

by Selenium Defi ciency ....................................................... 297 11.9 Effects of Selenium on Steroid Hormone Receptor Signaling

Pathways .............................................................................................. 297 11.9.1 Androgen Receptor (AR) Expression and Signaling ........... 297 11.9.2 Estrogen Receptor Signaling ................................................ 298

11.10 Effects of Selenium on Secretory Proteins Important for Angiogenesis and Invasion ............................................................. 299 11.10.1 Methylselenium-Specifi c Inhibitory Effect of VEGF

Expression ............................................................................ 299 11.10.2 MMP-2 and Other MMPs .................................................... 300

11.11 Possible Chemical Basis for Selenium Effects .................................... 301 11.11.1 Covalent and Noncovalent Modulation on Thiol Redox ...... 301 11.11.2 Global Protein Redox Modifi cation and ER Stress

Response Induced by MSeA ................................................ 302 11.12 Selenium in Cancer Therapy ................................................................ 303

11.12.1 Reduction of Side Effects of Drugs and Enhancement of Drug Effi cacy ................................................................... 303

11.12.2 A Phase I Study with SeMet and Irinotecan ........................ 303 11.12.3 Selenium as an Enhancer of Drug-Induced Apoptosis ......... 304

11.13 Summary and Implications .................................................................. 305 Acknowledgments ............................................................................................. 306 Abbreviations .................................................................................................... 306 References ......................................................................................................... 307

Mitogenic and survival signals initiated by polypeptide growth factors in mammalian cells are processed by receptors localized on the plasma membrane surface. These transmembrane receptors have a protein tyrosine kinase (PTK) activity domain that is localized at the cytoplasmic region of the protein molecule. The interaction of the growth factor ligands with the receptors induces their dimerization and activation through autophosphorylation. The activated PTK then activates one or multiple cytosolic signaling cascades including several protein kinase families, such as phosphatidylinositol 3-kinase-AKT (PI3K-AKT), extracellular signal regulated kinases (ERK), c-Jun N-terminal kinase (JNK), and stressactivated kinase (SAPK)-1/p38 mitogen-activated protein kinase (p38 MAPK). These kinases relay the signals from the cell surface to the nucleus to activate nuclear transcriptional factors, such as activating protein-1 (AP-1), which consists of Jun/Fos heterodimers, nuclear factor-kappa B (NF-κB), and p53 tumor suppressor

protein, resulting in altered gene expression patterns and cellular responses, such as cell cycle progression and suppression of cell death. In addition to the large polypeptide growth factors that bind surface receptors, small molecule hormone ligands can enter the cell and bind tissue specifi c receptors, such as the androgen receptor (AR) in the prostate and the estrogen receptor in the breast, to mediate specialized signaling in their target cells and organs.