Table Of ContentYusuf A. Hannun · Chiara Luberto
Cungui Mao · Lina Marie Obeid Editors
Bioactive
Sphingolipids
in Cancer
Biology and
Therapy
Bioactive Sphingolipids in Cancer Biology
and Therapy
Yusuf A. H annun • Chiara Luberto
Cungui Mao • Lina Marie Obeid
Editors
Bioactive Sphingolipids in
Cancer Biology and Therapy
Editors
Yusuf A. H annun Chiara Luberto
Stony Brook Cancer Center Department of Physiology & Biophysics
Stony Brook University Stony Brook University
Stony Brook , NY , USA Stony Brook , NY , USA
Cungui Mao Lina Marie Obeid
Department of Medicine Department of Medicine
Stony Brook University Stony Brook University
Stony Brook , NY , USA Stony Brook , NY , USA
ISBN 978-3-319-20749-0 ISBN 978-3-319-20750-6 (eBook)
DOI 10.1007/978-3-319-20750-6
Library of Congress Control Number: 2015947501
Springer Cham Heidelberg New York Dordrecht London
© Springer International Publishing Switzerland 2015
T his work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
T he use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
T he publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made.
Printed on acid-free paper
S pringer International Publishing AG Switzerland is part of Springer Science+Business Media
(www.springer.com)
We dedicate this volume to the memory of
our esteemed colleague Bob Bittman whose
commitment and scientifi c advancement of
sphingolipid research is undisputed and can
also be appreciated fi rst hand by his own
contribution to this book. His research will
be a legacy for years to come.
Yusuf, Lina, Chiara, and Cungui
Pref ace
T his volume presents and discusses the evidence regarding the roles and functions
of various sphingolipids (SLs), including ceramides and sphingoid bases and their
phosphorylated derivatives, and more complex SLs in the development, progres-
sion, and treatment of various cancers. (Gangliosides, a class of complex SLs com-
prising hundreds of different molecules, and of undisputed relevance in cancer
biology, are not discussed in depth in this volume.)
The modern revolution of molecular biology and biochemistry has brought us
the era of genomics and proteomics, and the rediscovered importance of cellular
metabolism and energetics in various diseases, including cancer. In turn, these have
led to the integrated study of metabolic pathways and the novel metabolomic
approach. More recently, the understanding of the bioactive functions of lipids in
pathophysiology has propelled the study of this class of molecules, historically
somewhat unrecognized, into the limelight. The appreciation of the metabolic inter-
connections among different lipid pathways has led us to the current era of lipido-
mics. Indeed, lipidomics has become the new frontier in the effort to uncover the
global imprint of each specifi c patho/physiological condition. Among the various
classes of lipids, SLs represent the youngest, but quite prolifi c, research domain.
The delay in the recognition of the functional signifi cance of lipids, in general,
and of sphingolipids, in particular, is largely due to the conceptual and technical
challenges that face researchers involved in SLs, challenges brought by the intrinsic
nature of these molecules, and of their metabolic pathways.
A t the conceptual level, fi rst, it is clear that bioactive SLs form a network of inter-
convertible metabolites. Thus, unlike “dedicated” signaling pathways such as the
paradigmatic cAMP pathway, bioactive SLs are metabolically interconnected so that
one lipid (e.g., ceramide) can be further metabolized to another lipid (e.g., S1P) which
often exerts opposing effects. Second, pathways of lipid metabolism are compart-
mentally, and often topologically, constrained. Therefore, understanding how they
function requires a careful determination of where they function. Third, the belated
molecular identifi cation of enzymes of SL metabolism has disclosed the existence
of a multiplicity of pathways involving these lipids (e.g., ceramide) that may show
vii
viii Preface
distinct regulation and distinct functions. Fourth, the chemico-physical properties of
lipids impose several barriers to their study. They are poorly soluble, which hinders
in vitro and cell studies. This also coerces their existence to specifi c subcellular mem-
branes. Moreover, accurately analyzing their levels requires sophisticated technolo-
gies, such as tandem mass spectrometry. Even their synthetic chemistry tends to be
an order of magnitude more complicated than other “soluble” molecules and, as such,
requires specifi c expertise. This is important not only for creating standards, but also
for generating cellular probes and lead enzyme inhibitors.
Research in the SL fi eld has overcome these challenges by adopting ever-
evolving experimental approaches and analytical methods that have proven invalu-
able to uncover a critical role for many of these lipids in physiology and
pathophysiology. Indeed, different SLs have been linked to the development of sev-
eral diseases such as diabetes, neurodegenerative diseases, emphysema, and infec-
tions, to mention a few. Notably, different bioactive SLs have also been linked to
initiation and/or progression of various cancers.
I ndeed, a large body of work has suggested that certain bioactive SLs, such as
ceramide and sphingosine, constitute t umor-suppressor lipids , whereas others, like
S1P, function as t umor-promoting lipids . This general hypothesis is buttressed by
increasing evidence that enzymes that attenuate ceramide and sphingosine or
increase S1P are increased in cancers, whereas those that increase ceramide or atten-
uate S1P are decreased in cancers. Many emerging studies show that interfering
with these pathways can exert profound effects on cancer cells (such as induction of
apoptosis, differentiation, tumor senescence, and regulation of angiogenesis).
In addition to an introductory overview that illustrates the key concepts of sphin-
golipid metabolism and SL-mediated signaling, and that serves as reference for all
other chapters, the book is divided into three main parts. The fi rst part addresses
how the SLs mentioned above are involved in the development of specifi c cancers,
each of which is treated in a stand‐alone chapter. Each chapter in this part covers
basic as well as clinical aspects of SLs or SL‐metabolizing enzymes in the context
of each different cancer. The discussion that centers on the basic experimental evi-
dence systematically addresses the specifi c involvement of the aforementioned SLs
in key cellular functions known to be altered in the complex processes that lead to
cancer (e.g., proliferation, the various forms of cell death, differentiation, senes-
cence, adhesion/migration, and multidrug resistance).
The second part focuses on the most innovative techniques/approaches for quan-
titative analysis and imaging of SLs and SL-metabolizing enzymes, including the
use of novel chemical probes.
The third and fi nal part discusses the potential diagnostic and/or prognostic value
of SL and/or SL-metabolizing enzymes and the potential benefi t of targeting SL
metabolism to develop novel cancer therapeutics for de novo treatment or to
overcome resistance to already-established regiments.
Stony Brook, NY, USA Yusuf A. Hannun
Chiara Luberto
Cungui Mao
Lina Marie Obeid
Contents
Basics of Sphingolipid Metabolism and Signalling ...................................... 1
Céline Colacios , Frédérique Sabourdy , Nathalie Andrieu-Abadie ,
Bruno Ségui , and Thierry Levade
Part I Roles and Functions of Sphingolipids in the Development
of Different Types of Cancers
Role of Sphingolipids in Hematological Malignancies:
Lymphoproliferative Disorders ..................................................................... 23
Hirofumi Sawai , Makoto Taniguchi , and Toshiro Okazaki
Role of Sphingolipids in Hematological Malignancies:
Myeloproliferative Disorders ......................................................................... 53
Sitapriya Moorthi and Chiara Luberto
Sphingolipids as Mediators of Breast Cancer Progression,
Metastasis, Response and Resistance to Chemotherapy ............................. 81
Benjamin Newcomb and Yusuf A. Hannun
Role of Sphingolipids in Non-melanoma Skin Cancer ................................ 107
Chih-Li Lin and Cungui Mao
Dysregulation of Sphingolipid Metabolism in Melanoma: Roles
in Pigmentation, Cell Survival and Tumor Progression .............................. 123
David Garandeau , Marguerite Mrad , Thierry Levade ,
Cristiana Perrotta , Nathalie Andrieu-Abadie , and Mona Diab-Assaf
Colon Cancer: The Role of Sphingolipid Metabolic Enzymes.................... 141
Hideki Furuya , Songhwa Choi , Lina M. Obeid ,
Toshihiko Kawamori , and Ashley J. Snider
Dietary Sphingolipids in Colon Cancer Prevention ..................................... 161
Eva M. Schmelz , Hui Zhou , and Paul C. Roberts
ix
