Mitochondria: The Anti- cancer Target for the Third Millennium

387 Pages·2014·5.8 MB·English

by  Jiri Neuzil

Jiri Neuzil · Shazib Pervaiz
Simone Fulda Editors
Mitochondria:
The Anti-
cancer Target
for the Third
Millennium
Mitochondria: The Anti-cancer Target
for the Third Millennium

Jiri Neuzil (cid:129) Shazib Pervaiz (cid:129) Simone Fulda

Editors
Mitochondria:
The Anti-cancer Target
for the Third Millennium
Editors
Jiri Neuzil Shazib Pervaiz
School of Medical Science School of Medicine
Griffi th University National University of Singapore
Southport , QLD , Australia Singapore, Singapore
Simone Fulda
Institute for Experimental Cancer
Research in Pediatrics
Goethe University
Frankfurt , Germany
ISBN 978-94-017-8983-7 ISBN 978-94-017-8984-4 (eBook)
DOI 10.1007/978-94-017-8984-4
Springer Dordrecht Heidelberg New York London
Library of Congress Control Number: 2014940078
© Springer Science+Business Media Dordrecht 2014
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Contents
1 Mitochondrion: A Novel Center for Cancer Cell Signaling ................ 1
Sumitra Miriyala , Aaron K. Holley , and Daret K. St. Clair
2 Exploiting BH3 Mimetics for Cancer Therapy .................................... 39
Donat Kögel
3 Regulation of Mitochondrial Function by MicroRNA ........................ 59
Marco Tomasetti , Lan-Feng Dong , and Jiri Neuzil
4 Mitochondrial Complex II in Cancer .................................................... 81
Katarina Kluckova , Jiri Neuzil , and Jakub Rohlena
5 Exploiting Celecoxib in Cancer Therapy .............................................. 105
Verena Jendrossek
6 Activation of Mitochondria-Driven Pathways by Artemisinin
and Its Derivatives .................................................................................. 135
Thomas Efferth
7 Vitamin E Analogues as Prototypic Mitochondria-Targeting
Anti-cancer Agents .................................................................................. 151
Lan-Feng Dong and Jiri Neuzil
8 Targeting Mitochondria of Cancer Cells: Mechanisms
and Compounds ...................................................................................... 183
Gang Chen , Helene Pelicano , Marcia A. Ogasawara ,
Feng Wang , and Peng Huang
9 Targets and Strategies for the Mitochondrial Assault on Cancer ...... 211
Lucia Biasutto , Ildikò Szabò , and Mario Zoratti
10 Emerging Anti-cancer Targets in Mitochondria .................................. 265
Petr Ježek , Katarína Smolková , Aleš Dvořák , and Tomáš Olejár
v
vi Contents
11 Relevance of Mitochondrial Functions and Plasticity
in Tumor Biology ..................................................................................... 291
Emilie Obre , Nadège Bellance , Caroline Jose , Giovanni Benard ,
Karine Nouette-Gaulain , and Rodrigue Rossignol
12 Crosstalk Between p53 and Mitochondrial Metabolism ..................... 327
Koji Itahana and Shazib Pervaiz
13 The Progression of Cardiomyopathy in the Mitochondrial
Disease, Friedreich’s Ataxia ................................................................... 349
Samantha Ting , Michael Li-Hsuan Huang ,
Sutharshani Sivagurunathan , and Des R. Richardson
Index ................................................................................................................ 379
Intro duction

The onset of the third millennium has witnessed unprecedented progress in molecular
medicine. Despite this fact, a number of pathologies remain an overwhelming burden
that is yet to be fully understood and, consequently, harnessed. This applies for some
of the most widespread and hard-to-manage pathologies, epitomized in particular
by neoplastic and neurodegenerative as well as cardiovascular diseases. Therefore,
new approaches and new targets are needed to progress in the fi ght against these
debilitating ailments.
D uring recent years, the resurgence of the importance of mitochondria as a
potential molecular target for the treatment of a variety of pathologies has been
seen. This is not all that surprising given the fact that mitochondria, the powerhouse
of the cells providing the majority of ATP as well as purveyors of cell death, control
numerous processes in the cell that touch on practically all aspects of its homeostasis.
Naturally, the research on mitochondria in the context of pathologies such as cancer
has undergone considerable progress, fuelled initially by the landmark discoveries
of Otto Warburg in the fi rst half of the nineteenth century.
T hat mitochondria are essential for the regulation of cellular bioenergetics and
relay the switch to the glycolytic phenotype of malignant cells has been known for
some time. However, only recently the molecular mechanisms of these processes
have started to be uncovered. Consequently, it has been suggested and supported by
a growing number of compelling reports that mitochondria are very promising tar-
gets for a number of therapeutic agents. In the context of mitochondria, these agents
have been termed ‘mitocans’, i.e. small compounds that exert their anti-cancer effect
by mitochondrial destabilization. These compounds show substantial promise as
potential anti- cancer drugs, and more and more research attests to this paradigm.
This book is dedicated to the recent advancement in mitochondria as an intriguing
target for human pathologies, focusing, with one notable exception, on cancer.
The fi rst chapter by Miriyala et al. discusses the central role of mitochondria in
signalling within cancer cells, followed by a chapter by Kögel on BH3 mimetics
as highly promising anti-cancer agents. The next chapter deals with complex II as an
intriguing target for cancer treatment, put together by Rohlena et al. This complex,
one of fi ve mitochondrial complexes of oxidative phosphorylation (OXPHOS), is at
vii
viii Introduction
the crossroads of the tricarboxylic acid cycle and OXPHOS, presenting a worthy
target to be explored in detail. Several ensuing chapters discuss individual (or group
of) agents acting on mitochondria, including celecoxib, artemisin and its deriva-
tives, as well as vitamin E analogues. Follow three subtly more general chapters on
more-or-less specifi c strategies targeting mitochondria by Chen et al., Biasutto et al.
and Ježek et al. Obre et al. discuss the plasticity of malignant cells in the context of
their bioenergetics and the mitochondrial function. Itahana and Pervaiz then focus
on the cross-talk between the ‘gatekeeper’ of the genome, i.e. p53, and mitochon-
drial function, a very important paradigm that has recently emerged. Notably, the
last chapter of the book has a non-cancer context. It is written by Ting et al. and
highlights the role of mitochondria in Friedrich’s ataxia, an autosomal recessive
inherited disease that causes progressive damage to the nervous system.
The topics of this book were chosen to cover in both rather general as well as
more specifi c manner the various aspects of mitochondria as important, emerging
targets for treatment of various human diseases, exemplifi ed here primarily by
malignancies. We hope that this book will contribute to the growing interest in mito-
chondria as intriguing organelles that are yet to be fully harnessed as an invariant
target for the therapy of a number of pathologies.
Mitochondria, Apoptosis and Cancer Research Jiri Neuzil
Group, School of Medical Science,
Griffi th Health Institute , Griffi th University,
Southport, QLD , Australia
and
Molecular Therapy Group, Institute of
Biotechnology , Czech Academy of Sciences ,
Prague , Czech Republic
Institute for Experimental Cancer Simone Fulda
Research in Pediatrics , Goethe-University ,
Frankfurt , Germany
Department of Physiology, Yong Loo Shazib Pervaiz
Lin School of Medicine ,
National University of Singapore , Singapore ,
Singapore
Chapter 1
Mitochondrion: A Novel Center for Cancer
Cell Signaling
Sumitra Miriyala , Aaron K. Holley , and Daret K. St. Clair
Contents
1 Introduction ...................................................................................................................... 2
2 Mitochondria in Cancer Development ............................................................................. 5
3 Electron Transport Chain ................................................................................................. 5
4 Mitochondrial DNA (mtDNA) Stability .......................................................................... 8
5 Mitochondrial Control of Innate and Adaptive Immunity ............................................... 10
6 Apoptosis.......................................................................................................................... 12
7 Tricarboxylic Acid (TCA) Cycle ..................................................................................... 14
8 Mitochondria as an Originator of Inside-Out Signaling .................................................. 16
9 Mitochondrial as a Signaling Generator/Recipient .......................................................... 18
9.1 Mitochondria in Outside-In Signaling .................................................................. 18
10 Transcription Factors ....................................................................................................... 19
10.1 Nuclear Receptors ................................................................................................. 19
10.2 Estrogen Receptor ................................................................................................. 19
10.3 Thyroid Hormone Receptor .................................................................................. 20
10.4 Cyclic AMP Response Element Binding Protein (CREB) ................................... 22
10.5 Signal Transducers and Activators of Transcription (STAT) ................................ 22
10.6 Other Transcription Factors and Nuclear Receptors ............................................. 23
11 Conclusions ...................................................................................................................... 24
References ................................................................................................................................ 24
S. Miriyala
Graduate Center for Toxicology , University of Kentucky , Lexington , KY 40536 , USA
Department of Cellular Biology and Anatomy , Louisiana State University Health Sciences ,
Shreveport , LA 71103 , USA
A. K. Holley
Graduate Center for Toxicology , University of Kentucky , Lexington , KY 40536 , USA
D. K. St. Clair (*)
Graduate Center for Toxicology, Markey Cancer Center, College of Medicine ,
University of Kentucky , 458 HSRB, 1095 VA Drive , Lexington , KY 40536-0305 , USA
e-mail: [email protected]
J. Neuzil et al. (eds.), Mitochondria: The Anti-cancer Target for the Third Millennium, 1
DOI 10.1007/978-94-017-8984-4_1, © Springer Science+Business Media Dordrecht 2014