Prostate Cancer Metabolism: From Biochemistry to Therapeutics

By Tomas Koltai, Stephan J. Reshkin, Fatima Baltazar and Larry Fliegel

Prostate Cancer Metabolism: From Biochemistry to Therapeutics shows the peculiarities of prostate cancer metabolism, emphasizing the targetable aspects – that have not been considered in conventional treatment protocols. The book specifically addresses treatment of the castration-resistant stage of prostate cancer proposing many repurposed drugs and nutraceuticals to complement, not replace, standard therapies. The large body of evidence supporting these concepts makes them deserving of further research and well-designed clinical trials. It discusses lipid, cholesterol, glutamine, and glucose metabolisms and their impact on prostate cancer. Additionally, it explains how current established drugs can be repurposed to improve treatment outcomes.

The concepts set out in the book, that deal with cancer at the cellular/molecular level, help identify new avenues of research and treatments to pursue that do not affect well-being whilst offer consistent benefits. Since most practicing physicians have not studied basic biochemistry since medical school, each chapter begins with a brief review of the topic to facilitate an understanding of the metabolically-oriented approach to targeting prostate cancer. Conventional treatments are not discussed here since they are covered in textbooks and specialized updates that abound in the medical literature.

It is a valuable resource for cancer researchers, oncologists, clinicians and members of biomedical field who want to learn more about prostate cancer metabolism and how to apply recent findings in the field to bedside.

• Explains the basic aspects of prostate cancer metabolism, including its biochemistry which has a pivotal role in clinical practice
• Discusses new drugs and nutraceuticals with a metabolism-centered approach
• Offers practical bedside approach in combination with molecular and biochemical fundamentals to help readers identify and provide the best treatment to their patients

• Language: English
• Publisher: Academic Press
• Release date: Jun 25, 2021
• ISBN: 9780323905510

Tomas Koltai

Tomas Koltai is Board Certified Specialist in Medical Oncology (1985), PhD in Chemistry (1997) and Master’s in Sciences in Molecular Oncology, University of Buenos Aires (2011). He has vast experience on cancer treatment at several positions: staff oncologist, Sanatorio Mater Dei, Argentina (1985-1990); Head of Oncology, Central Hospital of the Centro Gallego de Buenos Aires (1990-2000) and Medical Director, at the same institution (2000-2002); Head of the Department of Chemotherapy, National Social Services for Retirees, Argentina (2002-2014); Head of the Department of Oncology, Social Services of the National Food Workers Union, Argentina (2010-2014) and Medical Director at the same institution (2014-2016). He has authored several seminal publications on cancer and created the new “triple-edged cancer treatment”.

Book preview

Prostate Cancer Metabolism

From Biochemistry to Therapeutics

Tomas Koltai

Stephan J. Reshkin

Fátima Baltazar

Larry Fliegel

Table of Contents

Cover image

Title page

Copyright

Preface

Acknowledgment

Abbreviations used in this book

Chapter 1. Introductory words: cell metabolism and systems biology

Introduction

Cancer and systems biology

Understanding corticosteroids' effects in prostate cancer through systems biology

Prostate cancer metabolism is different

Conclusions

Why this book?

Chapter 2. Introduction to prostate cancer metabolism and treatment with nonconventional drugs

Introduction

Targeting prostate cancer metabolism

COX2 inhibition7: celecoxib

Pomegranate extracts

Ellagic acid

Statins

Conclusion 1

Conclusion 2

Conclusion 3

Conclusion 4

Conclusion 5

Conclusion 6

Final conclusion on statins

Conclusions

Chapter 3a. The conductors of the metabolic orchestra: part I

Introduction

Adenosine monophosphate kinase (AMPK)

mTORC1 (mammalian or mechanistic target of rapamycin complex 1)

The metabolic conductors in prostate cancer

AR–AMPK relationship

AR–PI3K/AKT/mTORC1 relationship

AR–AMPK–mTORC1 relationship

Conclusions

Chapter 3b. Phosphatase and tensin homolog deleted in chromosome 10: another metabolic regulator in prostate cancer?

Introduction

Metabolic functions of PTEN

Clinical implications

PI3K inhibitors

Conclusions

Chapter 4. Lipid metabolism part I: an overview

Introduction

Normal prostate metabolism versus prostate cancer metabolism

Prostate cancer metabolism

Fatty acid oxidation

Sphingosine and sphingosine kinase 1 in prostate cancer

Protumoral actions of sphingosine-1-phosphate

Inhibition of S1P and SK1

α reductases

Discussion

Statins and prostate cancer

PCa progression and lipid metabolism

Lipid peroxidation in prostate cancer

Future perspectives

Conclusions

Chapter 5. Lipid metabolism part II: sphingolipids and ceramides

Lipids: Introduction

Fatty acids

Phospholipase A2, AA, COX2, and cancer

Conclusions from Table 5.1

Lipoxygenase

Choline phospholipid metabolism in cancer

Sphingolipids and cancer

Conclusions

Chapter 6. Fatty acid synthesis and prostate cancer

Introduction

Synthesis of fatty acids (fatty acid synthesis pathways)

Mechanism of apoptosis induced by FAS inhibition

Integrating lipid synthesis in the metabolic framework

Lipid metabolism and cancer cell membranes

Fatty acid metabolism and prostate cancer

Clinical implications and conclusions

Chapter 7. Cholesterol metabolism in prostate cancer

Introduction

Cholesterol in the cell membrane

Cholesterol metabolism

Deregulation of cholesterol metabolism in prostate cancer

Liver X receptors and prostate cancer

Inhibiting the mevalonate pathway beyond HMG-CoA reductase

Increased mitochondrial cholesterol

Cholesterol's lysosomal trafficking

Lysosomotropic compounds with anticancer activity

Cholesterol and immunity

Statins and cancer

Discussion and conclusions

Future perspectives

Chapter 8. Glutamine metabolism in prostate cancer

Introduction

Glutamine and the experimental setting problems

Glutamine metabolism

The metabotropic glutamate receptor 1

mGluR1 and cancer

Environmental glutamate

Stopping the xCT–glutamate–mGluR1 circuit

Interfering with glutamine metabolism or its effects

Glutaminase inhibitors

Regulation of glutaminase

Summary and conclusions

Chapter 9. Carbohydrate metabolism in prostate cancer

Introduction

Metabolic behavior of cells in health and disease

The lactate shuttle in prostate cancer

Extracellular lactate as a key metabolite in prostate cancer progression

Therapeutic implications

Conclusions

Chapter 10. pH and electrolytes metabolism in prostate cancer

Introduction

Do these concepts also apply to PCa?

How the pH gradient is inverted in cancer in general and in prostate cancer in particular

Timing of pH changes

Interaction between pH and cancer progression

Extracellular acidity has multiple protumoral effects

How this knowledge may help achieve better therapeutic results

Interaction between hypoxia and pH gradient inversion

pH gradient inversion and proton exporters

How this system works in general and in prostate cancer in particular

Discussion

Conclusions

Chapter 11. Iron metabolism in prostate cancer

Introduction

Iron forms

Iron in cancer

Ferroportin-1 and hepcidin control systemic and intracellular iron levels

Fe functions in cancer cells: ribonucleotide reductase and DNA synthesis

Iron and metastasis

Iron chelators in cancer treatment

Iron metabolism linked strategies for treating cancer

Erastin

Iron metabolism in prostate cancer

Other proteins involved in iron metabolism

Therapeutic implications

Conclusions

Chapter 12. Androgen metabolism in castration-resistant prostate cancer

Introduction

Circulating androgen levels and prostate cancer risk

Androgen metabolism

Androgen synthesis in normal conditions

Androgen synthesis in prostate cancer

Androgen receptor

Androgen receptor activation

Androgen synthetizing machinery

Pharmaceuticals

The progression of prostate cancer to hormonal treatment resistance

Mechanism of resistance to androgen blocking

Clinical implications

Specific androgen receptor degraders (SARDs)

Nonclassical inhibitors of the androgen–androgen receptor axis

Discussion

Conclusions

Chapter 13. Summary, discussion, and conclusions

Introduction

Summary

Features specific to prostate cancer

Highlights of all chapters

Discussion

Promising research on metabolic targeting of prostate cancer

Possible drug combinations for the metabolic targeting of prostate cancer

Conclusions and final words

Index

Copyright

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Preface

We have come a long way since the 1920s when Charles Huggins, an urological surgeon with no research training, discovered that castration shrunk and defunctionalized the prostate. Now, almost 100 years later, chemical castration is an established treatment for advanced prostate cancer.

Along the history of Medicine and up to the 1940s, cancer treatment was exclusively in the hands of surgeons. Handcrafted ablation of the tumor was the only available resource. Nonsurgical cancers such as leukemia were simply ignored. Shortly after the end of World War II something changed: Sidney Farber's brinkmanship and keen observational ability lead to the discovery that an antifolate, aminopterine, could cure leukemia. It was the first drug to have an important effect on cancer, even if it did not cure it. And actually this drug targeted leukemic cells' metabolism as an antimetabolite. Thus, we may say that the history of chemotherapy started with the attack on metabolism, and this path had many successful results in cancer therapy in the last 70   years. Just to mention a few of these metabolic successes we have the development of drugs, such as methotrexate, 5-fluorouracil, asparaginase, capecitabine, pemetrexed, cytarabine, etc. They all act at some level of the cancer cell metabolism disgruntling its growth and proliferative objectives.

Targeting cancer metabolism is not a potential therapy. It is an already proven and developed way of treating cancer. Leukemia treatment is probably the best example of its success. However, at some point metabolic targeting research slowed down and remained enclosed in the nucleic acid metabolism. New knowledge on biochemistry and cell physiology has shown the possible benefits of targeting other metabolisms such as lipids and glutamine. This new knowledge has not been translated into bedside improvements. Sidney Farber took his discovery to the bedside immediately after his first observations, in a matter of a few weeks. Nowadays, after a metabolically active nontoxic anti-cancer drug is discovered it takes not years but decades until it reaches the patients. The best example of this very long time lag between discovery and clinical application is the case of cariporide. This is an inhibitor of the sodium–hydrogen exchanger 1(NHE1), probably the most powerful with proven lack of toxicity. Inhibition of NHE1 is a key strategy to slow down tumor growth and invasion. However, since it was proposed for the first time as an anti-cancer drug, 17   years went by without even a phase I clinical trial.

Every day a new promising metabolic drug target is being identified. Furthermore, an inhibitor or modifier for these new targets is being brought to light every day. But there is a long gap before these advances impact the clinical results, if they ever do.

To complicate things further, it is now clear that there is no one metabolism that suits all tumors at all times. The same tumor may have areas with different metabolisms going on at the same time, for example, coexistence of glycolytic and oxidative areas in the same tumor. Different stages of the tumor may show different metabolisms too. This is particularly so in prostate cancer. The metabolism of cancer cells is a function of the requirements of a tumor and the microenvironment availability of metabolites. In prostate we must add a third element: androgen signaling. Growth speed, oxygen and nutrients in the environment, androgen signaling, and genetic/epigenetic drivers, all together define these metabolic requirements.

Prostate cancer metabolism is slightly different from other cancer metabolisms and this difference offers a therapeutic advantage that we shall explore in this book. In prostate cancer its distinct metabolism supports the oncogenic phenotype.

There are some issues that may complicate prostate cancer targeting: it is not infrequent to find different metabolic phenotypes in the primary tumor and its metastases.

The objective of the book is to analyze prostate cancer metabolism, and in each step to identify effective ways of inhibiting or modifying metabolism in a way to curb further growth and induce apoptosis.

The association of basic research and clinical application has shown to be an effective way of introducing innovations into the therapeutic field. It is our intention to give the reader the fundamentals of basic biochemistry for understanding which are the targetable spots of prostate cancer metabolism and eventually use some existing and also new drugs that can accomplish the anti-cancer task.

Many known drugs with metabolic actions will be discussed. The two best known are statins and metformin. Both have accumulated many myths and scientific knowledge and sometimes it is not easy to separate good willing hope from hard science facts. However, precisely that will be done here. We shall underline the real values of these drugs and also show their shadows in metabolic cancer treatment.

How this book was written?

Most practicing physicians have forgotten many of the biochemical fundamentals they learned in medical school. This book cannot be fully understood without biochemistry basics at sight. Therefore, each chapter has a fairly detailed introduction with basic biochemical concepts but with a limited purpose: to understand how metabolism promotes the tumor and how specific drugs are able to curb it. Pathological biochemistry and its targeting will be analyzed in the frame of other molecular events, such as signaling and cellular modulators of prostate cancer metabolism. The objective of the book is to show the practicing oncologist, physicians, and urologist that there is a wealth of molecules that can target prostate cancer on a rational basis, alongside with classical treatments. Mainstream therapies will not be considered here. We think that there are exceptionally good publications on the issue. Our goal is to go one step beyond.

This book is the product of the cooperation of biochemist, basic researchers, and practicing physician. We hope that the objective will be reached.

Acknowledgment

We thank Julia Weiss for her revision and correction of this book.

Abbreviations used in this book

25-HC    25-Hydroxycholesterol

27-HC    27-Hydroxycholesterol

2DG    2-Deoxyglucose

4EBP1    eIF4E-binding protein

5-HETE    5-Hydroxyeicosatetraenoic acid

AA    Arachidonic acid

ABCA1    ATP-binding cassette transporter A1

ACC    Acetyl-CoA carboxylase

ACE inhibitors    Angiotensin-converting enzyme inhibitors

ACL    ATP citrate lyase

ACLY    ATP citrate lyase

ACTH    Adrenocorticotropic hormone

ADP    Adenosine diphosphate

AKT    Protein kinase B

ALS    Amyotrophic lateral sclerosis

AMACR    Alpha-methylacyl coenzyme A racemase

AMP    Adenosine monophosphate

AMPK    Adenosine monophosphate kinase

AR    Androgen receptor

AR-V7    Androgen receptor isoform variant 7

ART    Artemisinin and its derivatives

ASCT2    Alanine, serine, cysteine–preferred transporter 2

ATF4    Activating transcription factor 4

ATP    Adenosine triphosphate

bFGF    Basic fibroblast growth factor

CA    Carbonic anhydrase

CAFs    Cancer-associated fibroblasts

CA IX    Carbonic anhydrase 9

CAMKK    Calcium/calmodulin-dependent protein kinase kinase

CAT    Carnitine acetyltransferase

CA XII    Carbonic anhydrase 12

CBS    Cysthatione beta synthase

Ce    Celecoxib

CKα    Choline kinase alpha

CoA    Coenzyme A

COX2    Cyclooxygenase 2

CPT    Carnitine palmitoyl transferase

CREB    cAMP response element–binding protein

CRPC    Castration-resistant prostate cancer

CTP    Citrate transport protein

CYP7B1    Oxysterol alpha hydroxylase

DAG    Diacylglycerol

DCA    Dichloroacetate

DDIT4    DNA damage–inducible transcript 4

DFO    Desferrioxamine

DHEA    Dehydroepiandrosterone

DHT    Dihydrotestosterone

DMT1    Divalent metal transporter 1

eEF2    Eukaryotic elongation factor 2

eEF2K    Eukaryotic elongation factor 2 kinase

EGF    Epidermal growth factor

EGFR    Epidermal growth factor receptor

eIF2α    Eukaryotic translation initiation factor 2 alpha

eIF4E    Initiation factor 4E

EMT    Epithelial mesenchymal transition

ENO1    Alpha enolase 1

ER    Endoplasmic reticulum

ERS    Endoplasmic reticulum stress

ERα    Estrogen receptor alpha

ETC    Electron transport chain

FA    Fatty acid

FABP5    Fatty acid–binding protein isoform 5

FAD    Flavin-adenine dinucleotide

FADH2    Flavin-adenine dinucleotide reduced

FAS    Fatty acid synthase

FDA    Food and Drug Administration (USA)

FDG-PET    18 Fluoro-2-deoxyglucose PET scan

Fe    Iron

FKBP12    FK506-binding protein 12

FPT-1    Ferroportin 1

FRT    Fenretinide

GAPDH    Glyceraldehyde-3-phosphate dehydrogenase

GCN2    General control nonderepressible

GDH    Glutamate dehydrogenase

Gln    Glutamine

GLS1    Glutaminase 1

GLUT    Glucose transporter

GP130    G protein 130

GPCR    G protein–coupled receptor

GPDH    Glucose-6-phosphatedehydrogenase

GPNA    Gammaglutamyl-P-nitroamilide

GRH    Gonadotropin-releasing hormones

GTP    Guanosin triphosphate

HIF    Hypoxia-inducible factor

HIV    Human immunodeficiency virus

HMG-CoA    3-Hydroxy-3-methyl glutaryl coenzyme A

HMGCR    3-Hydroxy-3-methyl glutaryl coenzyme A reductase

HNE    4-Hydroxynonenal

HR    Hazard ratio (it is used as an equivalent to RR)

HRE    Hormone responsive element

IL-6    Interleukin-6

IL-6R    Interleukin-6-receptor

IRP1    Iron regulator protein 1

IRP2    Iron regulator protein 2

LAT1    L-amino acid transporter 1

LDH    Lactate dehydrogenase

LH    Luteinizing hormone

LKB    Liver kinase B

LOX    Lipooxygenase

LXR    Liver X receptor

MAGL    Monoacylglycerol kinase

MAPK    Mitogen-activated protein kinase

mCRPC    Metastatic castration–resistant prostate cancer

MCT    Monocarboxylate transporter

mGLUR1    Metabotropic glutamate receptor 1

MMP    Matrix metalloproteases

MRP1    Multidrug-resistance protein 1

MT1-MMP    Matrix metalloprotease 14

mTORC1    Mammalian target of rapamycin complex 1

NAD    Nicotinamide adenine dinucleotide

NADPH    Nicotinamide adenine dinucleotide phosphate reduced

NBC    Sodium bicarbonate cotransporter

Ndgr1    N-Myc downstream–regulated gene 1

NF-kB    Nuclear factor kappa B

NGF    Nerve growth factor

NHE1    Sodium–hydrogen exchanger 1

NHE3    Sodium–hydrogen exchanger 3

NPC1    Niemann–Pick type C1 protein

NPC1L1    Niemann–Pick type C1 like 1 protein

Nrf2    Nuclear factor erythroid 2–related factor 2

NSAIDs    Nonsteroidal antiinflammatory drugs

NSCLC    Non–small cell lung cancer

OXER    Oxoeicosanoid receptor 1

OXPHOS    Oxidative phosphorylation metabolism

PCa    Prostate cancer

PCSK9    Proprotein convertase subtilisin/kexin type 9

PDGF    Platelet-derived growth factor

PDH    Pyruvate dehydrogenase

PDK    Pyruvate dehydrogenase kinase

PDPK1    Phosphoinositide-dependent protein kinase 1

PET    Positron emission tomography

PFS    Progression-free survival

PGE2    Prostaglandin E2

PGH2    Prostaglandin H2

PI3K    Phosphoinositol 3 kinase

PIP2    Phosphoinositol bisphosphate

PIP3    Phosphoinositol triphosphate

PKM    Pyruvate kinase isoform M

PLA    Phospholipase A

PLC    Phospholipase C

PLD    Phospholipase D

PP    Proton pumps (V-ATPase proton pumps)

PPAR    Peroxisome proliferator–activated receptor

PPIs    Proton pump inhibitors

PPP    Pentose phosphate pathway

PSA    Prostate-specific antigen

PSMA    Prostate-specific membrane antigen

PTEN    Phosphatase and tensin homolog deleted in chromosome 10

PUFA    Polyunsaurated fatty acid

RANK    Receptor activator of nuclear factor kappa B

RAPALOGS    Inhibitors of mTORC1

RAPTOR    Regulatory-associated protein of mTOR

RCC    Renal cell carcinoma

Rheb    Ras homolog enriched in brain

ROS    Reactive oxygen species

RR    Relative risk

RR    Ribonucleotide reductase

RXR    9-Cis retinoic acid

S1P    Sphingosine-1-phosphate

S6K1    S6 kinase 1

SARDs    Specific androgen receptor degraders

SCAP    SREB cleavage–activating protein

SK1    Sphingokinase 1

SK2    Sphingokinase 2

Sp1    Specificity protein-1 transcription factor

SRE    Sterol responsive element

SREBP    Sterol regulatory element–binding protein

StAR    Steroidogenic acute regulatory protein

STARD3    StAR-related lipid transfer domain-3

STAT3    Signal transducer and activator of transcription 3

STEAP3    Ferric reductase

TfR1    Transferrin receptor 1

TGFα    Transforming growth factor alpha

Thr    Threonine

TL    Translocase

TRPC1    Vanillin cation channel

TSC    Tuberous sclerosis complex

TX    Tromboxane

ULK1    Unc-51-like kinase 1

USP    Ubiquitin-specific cysteine protease

VDAC    Voltage-dependent anion channel

VEGF    Vascular endothelial growth factor

VEGFR    Vascular endothelial growth factor receptor

VGSC    Voltage-gated sodium channel

VHL    Von Hippel–Lindau protein

XBP1    X-box protein 1

xCT    Cystine-glutamate antiporter

ZIP    Zinc uptake transporter

αKG    Alpha ketoglutarate

Chapter 1: Introductory words

cell metabolism and systems biology

Abstract

Cancer cell metabolism is a process that involves all cellular metabolism. It is not limited to altered glucose metabolism as it was originally believed in the decades from 1920 to 1960. Carbohydrates, lipids, amino acids, nucleic acids, proteins, energy balance, redox processes, electrolyte flux, and intra/extracellular pH, all suffer changes that allow the cells to maintain a highly proliferative course in the middle of very poor environmental conditions. Analyzing cancer metabolism as an isolated phenomenon offers few rewards. For a real understanding, it must be studied within a systems biology approach. This means that cancer metabolism is one part of a complex system that is formed by genetic and epigenetic changes, environmental conditions, and local tissue characteristics in a multicellular living organism that also has other organs. Furthermore, all these other elements influence the outcome of metabolic changes. This chapter will show why metabolism is not an isolated process and should be viewed as part of a complex entity from which it is not independent. This different way of looking at metabolism as part of a broad spectrum of changes will lead to an understanding of the reasons why corticosteroids, being inducers of chemoresistance in almost all tumors, are very useful in advanced prostate cancer. This is just one example of a systems biology approach.

Keywords

Cancer metabolism; Corticosteroids; Microenvironment; Prostate cancer; Systems biology

Introduction

Under normal circumstances, normal cells live in a comfortable environment in which there is no lack of nutrients or oxygen. In an ideal system, their life is under no big danger and they can fulfill their functions uneventfully. Whether they are glandular cells secreting, or epithelial cells sheltering, or neural cells transmitting, or immunocompetent cells protecting, they are able to perform their specific function when required. They face little or no existential threats. Their destiny is coded in their genes.

On the other hand, in an established malignant tumor, cancer cells live in a completely different world. Their life is not comfortable because their environment is harsh: acidic, depleted of oxygen and nutrients, abundant in toxic reactive oxygen species, usually under chemotherapeutic attacks, flooded with cytokines, chemokines, and proteolytic enzymes. ¹–³ And added to this, they are permanently urged to grow and proliferate, eventually to invade and metastasize further. ⁴ They permanently face death threats from the outside and interestingly from the inside. Their genes mutate in an accelerated fashion. Some of these mutations further accelerate other mutations creating a highly mutator phenotype. ⁵–⁹ Therefore, in the middle of these problems, they have one basic and essential function to fulfill: survival. And they become very good and efficient at it. But beyond survival, they also have to grow and proliferate.

No other functions are as important as survival, permanent growth, and eternal proliferation. This leads us to the 10 Commandments of the cancer cell.

The 10 commandments of cancer cells

1. Above all prevail and survive

2. Grow and proliferate no matter the circumstances

3. Use whatever tools at hand to survive

4. Invade anything that can be in your way

5. Go beyond all boundaries

6. In adversity mutate or adapt but always survive

7. Enslave your neighbors and make them work for you

8. Modify the environment in your favor

9. Forget about your host

10. Be immortal

After cancerization. the cell that was normal and living in a normal environment became a malignant cell that lives according to the precepts of the 10 commandments of the cancer cell. Its functions, whatever they were before cancerization, have been canceled. Its new functions are to:

• survive in an environment that becomes harsher as time goes by;

• grow in spite of poor oxygen and nutrient supplies;

• adapt to all internal and external circumstances; and

• proliferate indefinitely.

Not all malignant cells can cope with these demanding conditions and many die. However, the most fit remain, and a Darwinian selection takes place. This selection may take thousands of years in nature but in cancer it can be accomplished in a matter of days or weeks. The cells that survive in the adverse circumstances become more malignant, and more difficult to destroy. Survival capacity achieves a pinnacle in these cells, as does proliferation.

To achieve these surprising changes, it is not enough to undergo a gene mutation. The entire cell needs to change, starting from its morphology, following with its biochemistry and ending with its perpetuation. The mutated gene (or genes) is (are) the origin, but a mutation alone is unable to change the cell. Genes do not do anything by themselves, except express themselves through a codified message. From the mutated gene to the 10 commandments of the cancer cell there is a long road that involves signals, transmission of these signals, transcription factors, enhancers, enzymes, and metabolic pathways that need to be activated or repressed.

Cancer and systems biology

Approaching cancer merely as a genetic change is not enough. Undoubtedly, genetic change is the cause and root of cancer. But cancer will remain an elusive concept if it is not analyzed from the perspective of systems biology. Metabolism, as important as it is, is only one of the systems that change in cancer. To understand these modifications, we have to analyze them in the context of other systems that are also changing.

Systems biology is a view and a study of living organisms in which many different processes interact and converge to produce a single effect ¹⁰ and in this case that effect is cancer.

Cancer systems biology can be defined as the study of cancer as a complex adaptive system ¹¹ with properties that intervene in different systems. It means that systems biology brings together the complex network of genetic mutations, signaling pathways, and metabolic phenotypes needed in order to understand cancer as a holistic and integrated process (Fig. 1.1).

The goal of this approach is to translate this understanding to the bedside. ¹²

Each cancer researcher focuses on one special event in cancer. Systems biology tries to integrate all these special events into a mathematical model that would allow predictions and apply a better and more appropriate treatment. We are very far from this mathematical model; however, each forward step in research brings us closer to the desired model.

Metabolism is probably one of the branches of oncological research that is better suited to be approached from a systems biology angle.

In this book we shall see that cancers have a preference for fermentative glycolysis and exhibit high glucose uptake. What is behind this behavior? There are many issues involved. However, in an oversimplification, we shall consider only two transcription factors: hypoxia inducible factor-1 (HIF-1) and Myc. These transcription factors control the expression of most of the enzymes involved in the glycolytic chain. ¹³–¹⁶ Both may be overactive or overexpressed in cancer. Their overexpression, in turn, drives the overexpression of glycolytic enzymes. In many cases, the proper functioning of these enzymes may require a higher intracellular pH. How do HIF-1 and Myc do this? By acting as transcription factors on the promoter sequences of genes of the glycolytic enzymes. But why are they overexpressed? In the case of HIF-1 there are two possible causes: hypoxia or constitutional downregulation of the Von Hippel Lindau protein. Here we have a clear example of interrelation of environment (hypoxia) with a metabolic behavior (fermentative glycolysis) in the first case. In the second case, a genetic alteration of the Von Hippel Lindau gene releases HIF-1α that drives the glycolytic phenotype. ¹⁷–²⁰ In this case there is a direct interrelation between genes and metabolism. Different systems: genes, enzymes, transcription factors, and environment interact and create a unified response—the glycolytic phenotype. Many of the enzymes involved in glycolysis require a slightly alkaline intracellular milieu. Cancer cells create this milieu, thus optimizing the enzymatic function. ²¹–²³

Figure 1.1 Simplified approach to systems biology as the integrated study of the cell, its environment, and cellular physiology.

Looking at metabolism from a systems biology approach allows us to understand some processes in cancer metabolism that seem irrational at a first glance. For example, in carbohydrate metabolism we find that high glycolytic flux is one of cancer's characteristics. It was the first discovery in this terrain almost a 100 years ago. However, after degrading the glucose to lactate and obtaining two ATP molecules as energy gain, in some cases that same cell rebuilds glucose through a process known as the Cori cycle ²⁴ , ²⁵ and regenerates glucose, but at a cost of six ATPs. At a first glance this seems not to make sense from an energetic perspective: degrade glucose to gain two ATPs and then put together again the lactate to generate glucose at the cost of four ATPs.

However, if we look at it from a systems approach we will discover that:

1. glucose is used in this case not for energy production but for the generation of building blocks for the synthesizing machinery;

2. this synthesizing machinery is fed by the pentose phosphate pathway (PPP) as a major contributor;

3. not all the glucose taken up by the cell can follow the PPP because of enzymatic saturation;

4. therefore, an important part of the glycolytic flux ends in lactate;

5. the excess lactate is expelled by the monocarboxylate transporters. However, when too much lactate is being produced, it saturates the monocarboxylate transport system that extrudes lactate from the cell;

6. if all, or part, of this lactate were to remain inside the cell it would be toxic through the generation of an intracellular lactic acidosis;

7. the Cori cycle avoids an excessive load of lactate by reconverting it to glucose;

8. the Cori cycle increases glucose availability for the PPP, thus further increasing the glycolytic flux;

9. this happens at a price: four molecules of ATP are the cost of this process;

10. the cell's objective was achieved: enough building blocks for growth and proliferation were produced at some energy cost and without dangerous intracellular lactic acidosis.

A first conclusion is that we cannot analyze metabolic processes as compartmentalized phenomena, even though they physically take place in specific compartments. We have to do it as a contextualized phenomenon, such as the one we can obtain through systems biology. Metabolism cannot be analyzed solely as an energy balance equation. Energy balance is not the objective of cancer metabolism when the cell is in a synthesizing phase (Fig. 1.2).

Another example is arachidonic acid (AA). AA is a polyunsaturated fatty acid that forms part of the structure of membrane phospholipids. Under certain stimuli cytosolic phospholipase A2 releases AA from the membrane phospholipid. Three things can happen to AA ²⁶ :

1. it can be processed by cyclooxygenase enzymes producing prostanoids;

2. it can be processed by lipoxygenase producing leukotrienes;

3. it can remain unprocessed. In this last case AA can induce apoptosis²⁷.

Figure 1.2 A very simplified diagram of the biosynthetic objectives of aerobic glycolysis when the cell is in an active synthesis, and disregarding the energy loss produced by the Cori cycle. PPP, pentose phosphate pathway.

Which of the three metabolic possibilities will be followed by AA depends on the context (type of tissue) plus other external or internal signals which are not fully known. The third option, apoptosis, explains the reasons why AA is swiftly metabolized as soon as it is generated. Knowing what the future of AA will be depends on what is going on in other systems: membrane synthesis, activation of phospholipase A, autocrine and paracrine signaling, inflammatory process, and levels of oxygen. Its metabolism also depends on the tissue. For example, endothelial AA is mainly used to generate vasoactive eicosanoids (prostaglandins and leukotrienes). When oxygen levels are very high and for an extended time, AA participates indirectly in oxygen toxicity. ²⁸ Therefore, to study AA metabolism it is necessary to know the conditions in which this molecule lives.

This book will study metabolism with a systems biology approach whenever possible. Sometimes, data are not sufficient to know exactly why certain metabolic behaviors take place, thus making an integral view impossible. However, we shall study metabolism not only as a path of chemical reactions following an algorithmic schedule, but study it immersed in the microenvironment where things happen and are conditioned by other events as well.

In complex systems, such as those of mammals "the relations among their parts are dynamic, contextual, and interdependent." ²⁹ This interdependency is even more true in relation to metabolism. For example, there is no way to get an insight of the cancer cell's fermentative glycolysis just by studying the chemical algorithm that leads from extracellular glucose to lactate. That reductionist view of metabolism cannot explain why a cancer cell in much need of energy squanders large amounts of potential ATPs. Now if we insert this behavior in the tumor, and we can see that one of the objectives of metabolism in cancer is to generate enough biomass for proliferation, we would understand that one of the reasons for adopting a glycolytic phenotype is because it is the best metabolism for accelerated growth, even if it is energetically inefficient.

A reductionist approach would also sustain that cancer cells use fermentative glycolysis as its main energy source and use very little or no oxidative mitochondrial metabolism. ³⁰ A holistic approach would allow us to understand that metabolism is highly dynamic. When the cell needs to accumulate energy for what comes next, that is, biomass synthesis, it uses both fermentative glycolysis and mitochondrial oxidation, probably in the same proportion. But when the cell enters into a synthesizing phase, mitochondrial oxidative metabolism is turned down and glycolysis becomes the main pathway because it generates intermediate substances for biosynthesis.

The two phases of cancer cell metabolism

- Energy accumulation phase (presynthetic phase)

50% aerobic glycolysis   +   50% oxidative phosphorylation

- Biomass accumulation phase (synthetic phase)

75% aerobic glycolysis   +   25% oxidative phosphorylation

Normal mature cell metabolism

a

- Aerobic glycolysis <1%

oxidative phosphorylation   >   99%

Note: The percentages shown above are only estimates; the aim is to give an arbitrary but proportionate estimate for a better understanding.

---

a  There are few exceptions.

Glycolytic metabolism is also used by malignant cells as a mechanism to reduce oxidative stress. ³¹ Therefore, glucose metabolism must be analyzed in association with redox metabolism.

Metabolism, thus, has a cyclical movement, very much like the cell cycle. It is difficult to detect this cyclical conduct because most of the research works in a photographic manner. A picture is taken of the metabolism at a particular moment. To detect cyclic behavior, it is necessary to see the film rather than a picture. Another difficulty in detecting this behavior is the heterogeneity of tumors. Two adjacent cells may be engaged in different metabolic conducts. However, a holistic approach will show us that almost all the cancer metabolism behaves cyclically. These cycles are determined by cellular cycles. For example, choline is an essential substance for the synthesis of phosphatidylcholine, an important structural element of biological membranes. In 1994, Jackowski ³² showed that phospholipid synthesis and choline accumulation were coordinated with the cell cycle. In other words, phospholipid synthesis was cyclic. Who or what was behind this coordination has not yet been fully clarified. Therefore, we cannot understand the variable phospholipid metabolism, unless we analyze it in the context of the cell cycle. ³³

There are many controversial metabolic findings that can only be analyzed in a contextual manner. As an example, we have the case of the Nrf2-heme oxygenase-1 axis. Classically, it is considered a cytoprotective and detoxifying pathway ³⁴ ; however, in prostate and other cancers this pathway has a protumoral effect. ³⁵ It is both, but in different contexts. In normal cells it is antioxidant and protects cells from cancerization but in malignant cells it protects them from oxidative stress and chemotherapy attack. This led Jozkowicz et al. ³⁶ to call the Nrf2-heme oxygenase-1 pathway a false friend. Different contexts lead to different results, even when the mechanism of action remains unchanged.

Another example of different contexts. When a normal cell is detached from the extracellular matrix it has a high possibility of dying due to redox imbalance. Cancer cells found the way to inhibit death pathways and rebalance redox in order to survive. ³⁷ To acquire a real idea of redox metabolism, thus, again we must analyze it within its context.

Even hypoxia, with all its metabolic consequences, is cyclical in tumors. ³⁸–⁴⁰ Cyclical hypoxia has been found to be an important factor in spontaneous metastatic increase ⁴¹ , ⁴² and even inducing changes in gene expression. ⁴³ Blood flow into tumors is not stable. It is permanently modified by growth, new vessel formation (angiogenesis), obliteration of invaded vessels, vasodilating chemokines produced by the tumor, and stromal inflammatory reactions.

Understanding corticosteroids' effects in prostate cancer through systems biology

Corticosteroids have been used for more than 30 years for the treatment of castration-resistant PCa (CRPC). What for? According to De Santis and Saad ⁴⁴ :The importance of corticosteroids in mCRPC is due to their ability to manage adverse effects, reduce symptoms, and improve patients' quality of life. The antiinflammatory effects of corticosteroids reduce pain and edema in metastatic sites, downregulate ACTH secretion thus reducing adrenal androgen production, decrease angiogenesis and growth, ⁴⁵ and exert apoptotic effects in lymphoid cells. However, corticosteroids induce chemotherapy resistance in almost all tumors. ⁴⁶ Interestingly, the evidence shows that docetaxel-based chemotherapy associated with prednisolone in hormone-independent prostate cancer had superior results. ⁴⁷ Is this showing that prostate cancer behaves differently than other tumors? Again, we need a holistic view of the problem.

If we analyze the molecular context of PCa we will find that there is important cross-talk between the PI3K/AKT pathway and NF-kB activity. ⁴⁸ Corticosteroids are potent inhibitors of NF-kB activity. ⁴⁹ PCa growth and progression is stimulated by interleukin-6 (IL-6) ⁵⁰–⁵² and can be considered as a tumor in which the IL-6/IL-6R/GP130/STAT3 oncogenic hub is operative. Furthermore, IL-6 promotes ligand-independent activation of the androgen receptor. ⁵³ Corticosteroids also decrease IL-6 production and reduce IL-6/IL-6R/GP130/STAT3 signaling.

Systems biology lets us now understand why corticosteroids that increase resistance to chemotherapy actually improve the results of docetaxel treatment in androgen-independent PCa.

Prostate cancer metabolism is different

Prostate cancer has a peculiar metabolism that differs from many other tumors. It does not rely so much on fermentative glycolysis, as on lipogenesis, lipolysis, and glutaminolysis. This does not mean that glycolysis is not used. It only means that an important amount of the tumor's energy comes from glutaminolysis and lipolysis rather than from glycolysis. However, if any of these energy sources is inhibited, the prostate cancer cell switches to glycolysis. As a matter of fact, very advanced prostate tumors show a tendency to abandon lipogenesis and become more glycolytic. Probably, androgen receptors have a role in this shift. When prostate cancer becomes resistant to antiandrogen therapy, different isoforms of androgen receptor can usually be detected. ⁵⁴ , ⁵⁵ These new androgen receptors are resistant to antiandrogens ⁵⁶–⁵⁸ and they also have some different characteristics that are being slowly identified. There is no proof that the metabolic shift is caused by these isoforms or mutant receptors. We can only say that both appear at the same time, or close in time. This does not mean that mutant receptors shift metabolism but at least there are elements to suspect it.

It is not possible to conduct an in-depth analysis of prostate metabolism if we overlook the enormous influence that androgen receptors have on metabolism. ⁵⁹ For example, the lipogenic phenotype is one of the consequences of androgen signaling. ⁶⁰ Glutamine metabolism is modulated by androgen receptors and the transcription factor Myc. Androgen receptors are the master regulators of prostate cancer metabolism. ⁶¹ This is not found in other type of tumors, and makes prostate cancer metabolism unique.

This uniqueness is both a positive and negative factor for prostate cancer.

It is positive because it lets the cell fulfill the 10 commandments of the cancer cell. It is negative because it is more easily targeted without damaging cells with a different metabolic regime.

Oncologists are very aware of the capital role androgens and androgen receptors represent. Thus, a great and successful effort has been dedicated to the issue. Antiandrogen treatment has become part of the standard therapy of advanced prostate cancer. ⁶² It is very useful until resistance develops. However, the oncology community is not so aware of the fact that even under castration resistance there remains a wealth of nontoxic drugs that would still be useful to address prostate metabolism. Basic researchers have developed extensive knowledge on how to interfere in prostate cancer metabolism. This knowledge has not reached bedside treatments as yet.

This book intends to fill in the gaps between basic research and oncology practice.

The 10 commandments of the prostate cancer cell

(1) Obey your master regulators: androgen receptor and MYC⁶³,⁶⁴

(2) Inactivate or mutate PTEN⁶⁵,⁶⁶

(3) Amplify androgen receptors as much as possible⁶⁷

(4) Use glutamine and lipogenesis as a source of energy

(5) If they are not available use glucose⁶⁸

(6) Increase the expression of your lipogenic enzymes⁶⁹,⁷⁰

(7) Increase the expression of your glutaminolytic enzymes⁷¹,⁷²

(8) Increase the expression of your lipolytic enzymes⁷³

(9) Create a glutamate-rich environment⁷⁴–⁷⁶

(10) Glutathione is your friend⁷⁷,⁷⁸

Conclusions

Cancer metabolism is not an isolated process in malignant cells. It is a highly dynamic and gene-dependent phenomenon. This means that whenever we study any metabolic pathway we must analyze it as part of a complex network which is strongly influenced by a great number of other processes. In prostate cancer androgen receptors are the main influencers. Practicing oncologists know this well. The problem starts when the tumor becomes castration resistant. This is the beginning of the end. However, there is one more resource that has not been used so far: attacking the prostate cancer's metabolism.

The unique features of prostate cancer metabolism make it a targetable spot with little or no impact on normal cells.

Why this book?

The only rational way to understand the relationship between prostate cancer and metabolism is through a profound analysis of how lipid and glutamine metabolisms provide advantages to growth and proliferation.

This book will explore prostate cancer metabolism and analyze possible mechanisms and drugs to interfere with it. However, we must remind the reader that none of these possible treatments will solve the problem as a stand-alone drug. They may complement the established therapies as add-on pharmaceuticals in order to improve results. Some nutraceuticals like pomegranate extract, ellagic acid, and silibinin deserve further research; they have shown clear effects on lipid metabolism in prostate cancer.

Finally, we must underline that when conventional treatments are no longer effective pharmacological interventions on prostate cancer metabolism may add a new resource. The new generation of powerful fatty acid synthase inhibitors that can overcome castration resistance is particularly interesting in this sense.

There are very good books and articles on prostate cancer and its metabolism. Some analyze both issues together. However, most of them use a biochemical, biological, or clinical approach but not all three at the same time. This book is the product of the association of molecular biologists, a pharmacist and a clinical oncologist, thus approaching the subject in toto. The integral view of the prostate cancer problem and its tight connection with metabolism may open new avenues for treatment. The ability of some drugs to modify metabolism in prostate cancer has been known to basic researchers for many years. This knowledge has not arrived to the bedside as yet. The intention of this book is to urge clinical research in the field that may eventually be translated into innovative therapies in the near future.

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