Gewirtz / Holt / Grant Apoptosis, Senescence and Cancer

2. Auflage 2007
ISBN: 978-1-59745-221-2
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 599 Seiten, eBook

Reihe: Cancer Drug Discovery and Development

Apoptosis, Senescence and Cancer provides insight into established practices and research into apoptosis and senescence by thoroughly examining novel and emerging techniques and research in the fields of cell death pathways, senescence growth arrest, drugs and resistance, DNA damage response, and other topics which still hold mysteries for researchers. The volume is divided into six easy to follow sections. The first is Apoptosis and Alternative Modes of Cell Death, followed by chapters on Telomeres and Telomerase, Senescence, Genomic Instability and Tumorigenesis. The third part covers DNA Damage Response, Signaling Pathways and Tumorigenesis, while the fourth delves into Resistance and Sensitization. The book concludes with Established Cancer Therapies and a section which looks toward the future with Recent and Developing Cancer Therapies.In total, this volume provides basic scientists and clinicians with a deeper and more complete understanding of the cellular responses of malignancies which may determine the effectiveness of treatment, both in the initial stages of the disease as well as in disease recurrence.

Zielgruppe

Research

Autoren/Hrsg.

Gewirtz, David A.

Holt, Shawn E.

Grant, Steven

Inhaltsverzeichnis

Apoptosis and Alternative Modes of Cell Death.- The Intrinsic Pathway of Apoptosis.- The Extrinsic Pathway of Apoptosis.- Evaluating the Importance of Apoptosis and Other Determinants of Cell Death and Survival.- Mitotic Catastrophe.- Autophagy and Autophagic Cell Death.- Regulation and Function of Detachment-Induced Cell Death (Anoikis) in Cancer Progression and Metastasis.- Telomeres and Telomerase, Senescence, Genomic Instability, and Tumorigenesis.- Structure and Function of the Telomere.- Overview of Senescence.- Contributions of Telomerase to Tumorigenesis.- The Role of Telomeres in Genomic Instability.- DNA Damage Response, Signaling Pathways, and Tumorigenesis.- Overview of the DNA Damage Checkpoint.- Interactions Between Myc- and Cyclin-Dependent Kinase Inhibitors in Cancer.- Interplay Between ?H2AX and 53BP1 Pathways in DNA Double-Strand Break Repair Response.- DNA-Dependent Protein Kinase in Repair, Apoptosis, Telomere Maintenance, and Chemotherapy.- Resistance and Sensitization.- Resistance/Signaling Pathways.- Ceramide and Multidrug Resistance.- Chemo- and Radiosensitization Through Inhibition of PI3K/Akt Signaling.- The Advancement of Epidermal Growth Factor Receptor Inhibitors in Cancer Therapy.- Established Cancer Therapies.- Antimetabolites.- Topoisomerase I Poisons and Apoptotic Topoisomerase I-DNA Complexes.- Perturbations of Cellular Functions by Topoisomerase II Inhibitors.- The Significance of Poly-Targeting in Apoptosis Induction by Alkylating Agents and Platinum Drugs.- Contributions of Apoptosis and Senescence to Cytotoxicity Produced by Microtubule-Stabilizing Agents.- Tyrosine Kinase Inhibitors.- Recent and Developing Cancer Therapies.- Monoclonal Antibodies in Lymphomas.- Role of Apoptosis in Anti-Angiogenic Cancer Therapies.- PhotodynamicTherapy-Induced Apoptosis.- Modulation of TRAIL Signaling for Cancer Therapy.

Leseproben

5 Autophagy and Autophagic Cell Death (p. 92-93)

Mojgan Djavaheri-Mergny PhD,
Joëlle Botti PhD, and Patrice Codogno PhD

Summary

Macroautophagy or autophagy is a degradative pathway terminating in the lysosomal compartment after the formation of a cytoplasmic vacuole that engulfs macromolecules and organelles. During the last decade, progress made in our understanding of the molecular controls of autophagy has uncovered the importance of tumor suppressor molecules in the stimulation of autophagy. Downexpression of autophagy is an early event during tumorigenesis. However, the relation between autophagy and tumor progression seems to be more complex because cancer cells are able to trigger autophagy in response to various situations including changes in their extracellular environment and cancer treatments. The role of autophagy in cancer cells balances between two apparently opposite outcomes. Autophagy as a stress response mechanism can protect cancer cells from various insults. But autophagy can eliminate cancer cells by triggering autophagic cell death. These two aspects of autophagy will be discussed in this review.

Key Words: Autophagy, apoptosis, cell death, cancer, macroautophagy, lysosome, signal transduction.

1. INTRODUCTION

Autophagy is a lysosomal degradative mechanism occurring in different modes (chaperone-mediated autophagy, microautophagy, and macroautophagy) (1). This chapter is dedicated to macroautophagy (hereafter referred as to autophagy). Autophagy is a general and evolutionarily conserved vacuolar catabolic pathway terminating in the lysosomal compartment (2–4). It contributes to the quality control of cytoplasmic components by recycling macromolecules (autophagy is responsible for the turnover of long-lived proteins) and removing organelles when damaged or in excess (peroxisomes, mitochondria). From a cell biology standpoint, autophagy is characterized by the formation of a multimembrane-bound autophagosome that engulfs portions of the cytoplasm. The delimiting membrane of the autophagosome is derived from an ‘isolation’ membrane or phagophore of unknown origin (5). In mammalian cells, most autophagosomes can fuse directly with lysosomes or merge with endocytic compartments (6,7) to form an amphisome where the sequestered material is denatured because of the acidic environment. The final step is the fusion of amphisomes with the lysosomal compartment where the sequestered material is degraded.

The discovery of autophagy by de Duve and Wattiaux (8) was contemporary with that of lysosomes. The physiological importance of autophagy in maintaining cell homeostasis in organs such as liver and in cultured cells rapidly emerged (9,10). At the same time, the term autophagic cell death or type II programmed cell death (PCD II) was introduced to describe a cell death different from apoptosis or type I PCD (PCD I) (11,12). From these data, it appeared that autophagy is a cell response to stress, which under certain circumstances can lead to cell death. However, the precise role of autophagy as a cell death mechanism remains to be explored (13). Identification of its molecular machinery and signaling pathways has shed some light on the importance of autophagy in physiological processes and diseases (1,2,14). Among the autophagy-related (ATG) genes, discovered in yeast and almost integrally conserved in all eukaryotic phyla, which control the formation of the autophagosome (15), beclin 1 (the mammalian ortholog of the yeast ATG6) is a tumor suppressor gene that contributes to a complex with the class III phosphatidylinositol-3- kinase (PI3K) to the formation of the autophagosome (16,17). Other tumor suppressor gene products [p53, PTEN, TSC1/TSC2, death-associated protein kinase (DAP kinase)] are involved in the control of autophagy (18). Interestingly, autophagy is also stimulated in cancer cells by ceramide (19,20), a tumor suppressor lipid (21).