editorial metabolism and cancer: old and new...

Hindawi Publishing CorporationInternational Journal of Cell BiologyVolume 2013, Article ID 293201, 2 pageshttp://dx.doi.org/10.1155/2013/293201

EditorialMetabolism and Cancer: Old and New Players

Claudia Cerella,1 Carine Michiels,2 Roderick H. Dashwood,3

Young-Joon Surh,4 and Marc Diederich4

1 Laboratoire de Biologie Moleculaire et Cellulaire du Cancer (LBMCC), Hopital Kirchberg, 9 rue Edward Steichen,L-2540 Luxembourg, Luxembourg

2 Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for LIfe Science (NARILIS),University of Namur, 5000 Namur, Belgium

3Cancer Chemoprotection Program, Linus Pauling Institute, 307 Linus Pauling Science Center, Oregon State University,Corvallis, OR 97331, USA

4Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University,Seoul 151-742, Republic of Korea

Correspondence should be addressed to Claudia Cerella; [email protected]

Received 9 June 2013; Accepted 9 June 2013

Copyright © 2013 Claudia Cerella et al.This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Altered metabolism represents one of the oldest hallmarksassociated with cancer. The aberrant metabolic profile dealsprimarily with the well-known switch of transformed cellstowards aerobic glycolysis from mitochondrial oxidativephosphorylation. In addition, it deals with the exacerba-tion of several biosynthetic pathways interconnected withthe increased glycolytic flux, eventually conferring selectivemetabolic advantages.

The distinctive and ubiquitous nature of this alteredmetabolic profile expressed by cancer cells from variousorigins or tissues turns the modulation/reversion of theseaberrations as an amenable strategy for new anticancertherapies. Despite Otto Warburg’s pioneering observations,targeting cancer cell metabolism for therapeutic purposesstill remains theoretical. Several factors have contributed tothis situation. Primarily, for many years, cancer has beentreated as a homogeneous and too simplistic cellular system,where the impairment of proliferation/viability of the mostabundant differentiated cancer cells has been extensivelypursued. This approach, however, has not been successfulin preventing tumour relapse. Cancer is nowadays consid-ered a complex network, including cancer cells at differentstages of differentiation, as well as noncancer cells fromthe tumour microenvironment. These cells exert specificfunctions further sustaining cancer progression, bymaintain-ing a proinflammatory environment, by inducing activation

of angiogenesis and by evading immune responses. Thecellular heterogeneity implies more subtle forms of mutualinteraction and communication among different cells andwith the microenvironment, which may be the niche forfuture innovative anticancer therapeutic interventions.

In this renewed view of cancer etiology, unexpectedcrosstalk is emerging betweenmetabolicmediators/processesand pathological alterations.

This special issue focuses on “Metabolism and cancer:old and new players” and intends to stimulate the discus-sion about new emerging targetable mediators of cancermetabolism and to evaluate possible noncanonical roles ofold players in tumorigenesis as well as in cancer metabolism.

The impairment of cancer cell viability by induction ofcell death remains the final outcome of many anticancerstrategies. Besides apoptosis, other modes of cell deathhave been defined and are attracting interest as alternativetherapeutically exploitable approaches to impact apoptosis-resistant forms of cancer.The review by S. Fulda, “Alternativecell death pathways and cell metabolism,” draws attention tothe programmed form of necrosis, namely, necroptosis, anddiscusses the relevance of metabolic pathways involved in itsmodulation. The author suggests a possible interconnectionbetween alterations of redox signaling pathways mediatingnecroptosis and mitochondrial impairment, which impliesthe latter as a crucial regulator of redox imbalance.

2 International Journal of Cell Biology

An ideal anticancer therapy should be able to efficientlytarget cancer stem cells. This requires the discovery ofmarkers selectively identifying malignant stem cells. Thereview by C. Pecqueur et al., “Targeting metabolism to inducecell death in cancer cells and cancer stem cells,” addressesthe relationship between cancer cell metabolism and evasionfrom apoptosis by comparing the main features of cancercells and cancer stem cells. The authors correlate the peculiarmetabolic characteristics of these two types of cancer cellswith their ability to evade apoptosis.

Over the last 10 years, noncanonical roles formany factorsimplicated in apoptosis were published. The family of B-cell lymphoma-2 (Bcl-2) proteins represents one of the mostinteresting examples, with several members exhibiting essen-tially pro- and apoptotic functions. The paper by J. Michelset al., “Functions of Bcl-xL at the interface between cell deathandmetabolism,” reviews new and intriguing properties of theBcl-2 homolog Bcl-xL (B-cell lymphoma extra-large) linkedto regulation of bioenergetic metabolism, which in turn con-trols important processes including mitochondrial ATP syn-thesis, Ca2+ flux, autophagy, mitosis, and protein acetylation.

Cancer cells rely on glycolysis rather than on oxidativephosphorylation to fulfill their energy needs. In conditionsof glucose deprivation, however, cancer cells may reactivatemitochondrial bioenergetics as part of a prosurvival strategy.The study by R. Palorini et al., “Mitochondrial complexI inhibitors and forced oxidative phosphorylation synergizein inducing cancer cell death,” shows that mitochondrialcomplex I inhibitors sensitize cancer cells to cell deathunder glucose depletion. Interestingly, combined treatmentsaffecting glycolysis and leading to mitochondria impairmentare ineffective on immortalized cells or cancer cells cultivatedunder high glucose conditions. Their results suggest that theforced switch from glycolysis to oxidative phosphorylationcombined with the use of mitochondrial inhibitors maybe used as alternative therapeutic approach to increase thesensitivity of cancer cells to death.

Identification of specific metabolic intermediates as tar-gets for future anticancer treatments may be at the basisfor attempting a reversal of tumor metabolism to normalconditions, with the rationale of impairing cancer growth.Pyruvate kinaseM2 (PKM2) catalyzing the final rate-limitingreaction of glycolysis currently attractsmuch interest becauseof its multiple emerging intracellular functions. The reviewby N. Wong et al., “PKM2, a central point of regulationin cancer metabolism,” gives an overview of our currentknowledge about this important enzyme, discussing severalof its potential contributions to tumorigenesis.

A limiting factor in exploiting cancer metabolism fortherapeutic purposes is the lack of availability of agentsacting as specific modulators of cancer metabolism. Thereview by C. Cerella et al., “Natural compounds as regulatorsof the cancer cell metabolism,” covers this aspect, focusingon natural compounds as untapped potential regulators ofcancer cell metabolism.The authors discuss some of themostimportant pathways and factors implicated in altered cancermetabolism and give an overview of compounds extractedfrom natural sources potentially targeting these differentaberrantly regulated metabolic key intermediates.

The link between obesity, insulin resistance, and canceris explored from different sides in three papers of thisspecial issue, interestingly dealing all with hormonal formsof cancer.The paper by C. Brosseau et al., “Role of insulin-likegrowth factor binding protein-3 in 1, 25-dihydroxyvitamin-D

3-

induced breast cancer cell apoptosis,” aims at identifying themechanisms involved in 1, 25-dihydroxyvitamin D

3-induced

apoptosis in breast cancer cells. Their strategy suggests a rolefor insulin-like growth factor binding protein-3 (IGFBP-3) invitamin D-induced apoptotic signaling and the involvementof impaired secretion of IGFBP-3 in acquired chemoresis-tance.

The review by J. S. Byun and K. Gardner, “C-terminalbinding protein: a molecular link betweenmetabolic imbalanceand epigenetic regulation in breast cancer,” introduces thereader to the concept of metabolic transduction by stressingthe link between shifts in carbohydratemetabolism and alter-ations in epigenetic regulatory mechanisms. In particular,these authors investigate the family of transcriptional repres-sors called C-terminal binding proteins (CtBPs), whose func-tion is controlled by NAD+ levels, as an example of factorsinteracting and modulating the activity of different histonedeacetylases (HDACs) depending on the metabolic status.

Finally, the review by J. H. Gunter et al., “New play-ers for advanced prostate cancer and the rationalisation ofinsulin-sensitising medication,” points to the roles played bymetabolic disorders (especially related to insulin resistance)in favoring anticancer treatment failure and consequenthigher cancer-specific mortality. The authors discuss thepromising use of insulin-sensitizing drugs as potential anti-cancer agents to be used in combinational therapies.

Although alterations in cellular metabolism are an oldacquaintance in cancer etiology, we still need to do morebefore we can translate our knowledge into new and specificanticancer therapies. This final outcome will mostly dependon an in-depth identification of the mutual modulationbetween metabolism processes and factors that regulateproliferation and death/survival of cancer cells. With thisspecial issue, we hope to offer new and relevant insightstowards a critical reevaluation of this rapidly moving field.

Claudia CerellaCarine Michiels

Roderick H. DashwoodYoung-Joon SurhMarc Diederich

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