Apoptosome: An Up-and-coming Therapeutical Tool

326 Pages·2010·5.92 MB·English

by  Virve Cavallucci

Apoptosome
Francesco Cecconi Marcello D’Amelio
●
Editors
Apoptosome
An up-and-coming therapeutical tool
Editors
Francesco Cecconi Marcello D’Amelio
Dulbecco Telethon Institute Laboratory of Molecular Neuroembryology
at the Department of Biology IRCCS
University of Rome “Tor Vergata” Fondazione Santa Lucia
Rome Rome
Italy Italy
[email protected] [email protected]
ISBN 978-90-481-3414-4 e-ISBN 978-90-481-3415-1
DOI 10.1007/978-90-481-3415-1
Springer Dordrecht Heidelberg London New York
Library of Congress Control Number: 2009941845
© Springer Science+Business Media B.V. 2010
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Preface
Apoptosis, a form of programmed cell death, is a highly regulated process of cell
suicide and plays a fundamental role both in the embryonic development and the
homeostasis of the adult organism. The apoptotic program is executed by a family
of proteases known as caspases, which lead the cell to die in an orderly fashion by
cleaving a large number of cellular substrates. Analysis of the patterns of caspase
activation following different apoptotic stimuli has revealed two main pathways:
the death receptor pathway and the mitochondrial pathway. In the context of mito-
chondrial pathway the apoptosome has been established as a crucial factor in the
control of apoptosis, and aberrant apoptosome function has been implicated in
development defects and many diseases.
The aim of The apoptosome, an up-and-coming therapeutical tool is to present
recent developments in the understanding of the apoptosome and its regulation
under physiological, developmental, and pathological conditions.
The book starts with an exhaustive description of the apoptotic machinery and
an in-depth analysis of apoptosis both under physiological and pathological condi-
tions in which the equilibrium life-death is dysregulated. Therefore, the apopto-
some becomes the book’s main protagonist. Chapters 2–4 present and discuss the
major advances in the understanding of apoptosome structure and both biological
and chemical regulation. Chapter 5 addresses the challenge of implementation of
RNAi for the dissection of apoptotic cell death pathways and in experimental thera-
peutic approaches using apoptosis mediators as a target. Chapters 6–12 focus on
some important key molecules involved in apoptosome regulation and discuss them
in apoptosis-based therapies at the preclinical stage. Chapter 13 illustrates the role
of proteins controlling mitochondrial morphology in the regulation of apoptotic
events and discusses how the tight control of mitochondrial dynamics is crucial for
the proper function of the cell.
The last three chapters deal with the crucial transition “From Bench to Bedside.”
Basic research scientists are working to understand the molecular mechanisms of the
disease to be treated, and to unravel the underlying cause of the pathological condi-
tion. They try to understand how the genes are altered, how these alterations lead to
the production of unhealthy proteins and how these proteins interacting with each
other cause a gain or loss of a specific biological function and finally how this altered
function affects the patient. This knowledge is the basis for treating the problem.
v
vi Preface
Nevertheless the results of basic research cannot remain in a mere state of print
indefinitely; Papers need to have an application to real-life human situation and to
translate into developing effective therapies. Without that intersection between
basic science and the clinic, discoveries made at the research bench may prove
finally irrelevant. In this regard the last three chapters, beside providing an over-
view of the Translational Research and Drug Discovery Process, summarize the
main contributions of the application of knowledge about the apoptosome to the
development of therapeutic interventions, even though only a few compounds tar-
geting apoptosome have been approved by FDA for starting clinical trials.
Recognized authorities in their respective fields, the authors of the various chap-
ters have made significant contributions to improving our understanding of apopto-
some structure and pharmacological manipulation.
As in most multiauthored books, there is some overlap between the individual
chapters. This is not necessarily a defect, providing, rather, the reader with the
opportunity of understanding the same topic from different angles, thanks to the
writers coming from various scientific background.
We wish to thank all the contributors to this book and the many reviewers of the
manuscript. We also especially thank all the authors for respecting the often tight
deadlines requested.
Francesco Cecconi
Ph.D. in Molecular and Cell Biology
Marcello D’Amelio
Ph.D. in Neuroscience, M.Sc. in Clinical Research
Foreword
The field of apoptosis research has grown over the last 15 years from a collection of
tantalizing observations to the recognition of clearly defined signaling events that
define this critical signaling pathway from its beginning to its end. My personal his-
tory in the field covers the mechanisms that regulate some of the key central com-
ponents, the caspases. Through biochemical and structural tactics we and other
groups worldwide have been able to unravel the processes that the pivotal cellular
device known as the apoptosome plays in the apoptotic cell fate decision. Mutant
mice of the apoptosome components have provided a wealth of novel information,
assigning to almost all of these proteins a single (or multiple) function(s) in vivo.
Moreover, these discoveries have revealed a number of subtle pathways of apopto-
some regulation, which may be targeted to interfere with a plethora of pathogenetic
processes involved in human diseases. These range from cancer ontogenesis and
progression, to infectious diseases and inflammation, to neural disorders and neuro-
degeneration. The combined biochemical, biological and genetic knowledge base
paves the way to unraveling the precise mechanism of action of the apoptosome and
its effectors, enabling the design of new small molecules, pharmacophores or pepti-
domimetics, that may turn out to be useful in biomedicine. Much of this information
is assembled in ‘The apoptosome, an up-and-coming therapeutical tool’, marking a
turning point from the history to the future of apoptosis research. Only now, thanks
to the advanced tools and approaches we possess for generating pharmacological
compounds, are we beginning to grasp the fundamentals of apoptosome manipula-
tion in biomedicine and to appreciate how amazingly far-reaching the apoptosome
machinery is in development control, tissue homeostasis and pathogenesis. Although
a complete account of what has been achieved in this huge and daily growing area
is impossible, the new insights and progress in the field of apoptosis and apoptosome
research are amply documented in this timely book. The book should be useful for
everybody who wants to learn about the fascinating new insights into the biology of
cell death and survival and the pathogenesis of human diseases.
Professor Guy Salvesen, Ph.D.
Director, Program on Apoptosis and Cell Death Research
The Burnham Institute for Medical Research
San Diego, CA, USA
vii
Contents
1 Physiological and Pathological Role of Apoptosis .................................. 1
Virve Cavallucci and Marcello D’Amelio
2 Apoptosome Structure and Regulation ................................................... 27
Elisabetta Ferraro, Claudia Fuoco, Flavie Strappazzon,
and Francesco Cecconi
3 Chemical Regulation of the Apoptosome: New Alternative
Treatments for Cancer .............................................................................. 41
Kelvin Cain
4 Molecules That Bind a Central Protein Component
of the Apoptosome, Apaf-1, and Modulate Its Activity .......................... 75
Laura Mondragón, Mar Orzáez, Anna Gortat, Monica Sancho,
Angel Messeguer, María Jesús Vicent, and Enrique Pérez-Payá
5 Regulation of Cell Death and Survival by RNA
Interference – The Roles of miRNA and siRNA ..................................... 95
Paul Lingor
6 Beneficial Role of Taurine Against Myocardial
Apoptosis During Ischemic Injury .......................................................... 119
Takashi Ito, Stephen W. Schaffer, and Junichi Azuma
7 BAG3 Protein: Role in Some Neoplastic Cell Types
and Identification as a Candidate Target for Therapy .......................... 137
Maria Pascale, Alessandra Rosati, Michelina Festa, Anna Basile,
Morena d’Avenia, Antonia Falco, Gaetano Torino,
and Maria Caterina Turco
8 Targeting Survivin in Cancer Therapy: Pre-clinical Studies ................ 147
Marzia Pennati, Marco Folini, and Nadia Zaffaroni
ix
x Contents
9 Hsp70 and Hsp27: Emerging Targets in Cancer Therapy .................. 169
Anne Laure Rérole, Anne Laure Joly, Dominique Thuringer,
and Carmen Garrido
10 Role of the RNA-Binding Protein HuR in Apoptosis
and Apoptosome Function ...................................................................... 203
Yuki Kuwano, Imed-Eddine Gallouzi, and Myriam Gorospe
11 Acetylcholinesterase as a Pharmacological Target
in Cancer Research ................................................................................. 221
Sang Eun Park and Young Hyun Yoo
12 Putative Role of HCA66, A New Apaf-1 Interacting Protein,
in the Physiopathology of NF1 Microdeletion
Syndrome Patients .................................................................................. 237
Patricia Rigou, Audrey Faye, and Jean-Luc Poyet
13 Cristae Remodeling and Mitochondrial Fragmentation:
A Checkpoint for Cytochrome c Release and Apoptosis? ................... 253
Luca Scorrano
14 Apoptosome Pharmacological Manipulation: From Current
Developments in the Laboratory to Clinical Implications .................. 271
Marcello D’Amelio and Francesco Cecconi
15 The Therapeutic Role of Taurine
in Ischaemia-Reperfusion Injury ........................................................... 283
Ross Kingston
16 Targeting Survivin in Cancer Therapy: Clinical Considerations ....... 305
Tetsuhiro Tsuruma, Hidekaz Kameshima, Yuji Iwayama,
Toshihiko Torigoe, Yoshihiko Hirohashi, Noriyuki Sato,
and Koichi Hirata
Index ................................................................................................................. 321
Chapter 1
Physiological and Pathological Role
of Apoptosis
Virve Cavallucci and Marcello D’Amelio
Abstract Apoptosis plays a crucial role in tissue homeostasis, development and

many diseases. The relevance of Apaf1, the molecular core of apoptosome, has
been underlined in mitochondria-dependent apoptosis, which according to a growing
body of evidence, is involved in various pathologies where the equilibrium of
life-and-death is dysregulated. The current chapter, besides providing an overview
of the apoptotic machinery, will focus on knockout and knockin studies of key
components of the apoptosis cascade, and analyses of the apoptosis dysregulation
in many pathological conditions such as neurodegeneration, cancer, heart attack,
autoimmune disease and virus infections.
Keywords Apoptosis, mitochondrial pathway, pro-apoptotic factors, anti-apop-

totic factors, apoptosis dysregulation, life-death decision.
1.1 Introduction
Programmed cell death (PCD) is a finely regulated process essential for embryonic
development and maintenance of tissue homeostasis in multicellular organisms.
Apoptosis, the most well-defined type of PCD pathway, is characterized by specific
biochemical and morphological changes including chromatin condensation, cell
shrinkage, membrane blebbing, DNA fragmentation, and formation of apoptotic
bodies subsequently taken up by macrophages. Moreover, apoptotic cell death
involves the active cellular process; this is in contrast with necrosis, in which the
death is uncontrolled and causes an inflammatory response (Wyllie et al. 1980;
V. Cavallucci and M. D’Amelio
Dulbecco Telethon Institute at the Department of Biology, University of Rome ‘Tor Vergata’,
00133 Rome, Italy
V. Cavallucci and M. D’Amelio (*)
Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy
e-mail: [email protected]; phone [phone]; fax [phone]
F. Cecconi and M. D’Amelio (eds.), Apoptosome: An up-and-coming Therapeutical Tool, 1
DOI 10.1007/978-90-481-3415-1_1, © Springer Science+Business Media B.V. 2010