Table of Contents 1 The Hallmarks of Cancer: 9 – Reprogramming Energy Metabolism 2 ABOUT BUDDHINI SAMARASINGHE 2 Respiration 101 2 TAGS 2 RECENT POSTS 3 Aerobic Glycolysis 3 CATEGORIES 3 ARCHIVES 3 STEM WOMEN 3 Greedy for Glucose 4 The Mechanisms of a Metabolic Switch 5 YOU MAY ALSO LIKE... 7 “Sticky Balls” and Cancer Therapy 8 Cancer Stem Cells 8 Men at Greater Risk for Cancer than Women 8 1 RESPONSE 8 LEAVE A REPLY 8
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BY BUDDHINI SAMARASINGHE · PUBLISHED OCTOBER 10, 2014 · UPDATED Samarasinghe, Professor of Chemist ry OCTOBER 15, 2014
This article originally appeared on the Scientific American Guest Blog.
The Hallmarks of Cancer are ten underlying principles To search type and hit enter
shared by all cancers. The ninth Hallmark of Cancer is
defined as “Reprogramming Energy Metabolism”. ABOUT BUDDHINI SAMARASINGHE Uncontrolled growth defines cancer. Growth requires a cancer’s cells to replicate all of their cellular components; their DNA, RNA, proteins and lipids must all be doubled in order to divide into daughter cells. Of course, this process requires energy. Cancer cells must adjust their metabolism accordingly, to enable this frenzied growth.
Respiration 101 Cells require energy to absorb nutrients, to react to changes in their surroundings, to maintain their internal environment, grow, and replicate. Energy is obtained from I am a molecular biologist wit h experience breaking down nutrients through a process of metabolic in cancer research. I st udied at t he reactions known as respiration. This energy is stored in Universit y of Bat h, earned my PhD at t he small molecules known as adenosine triphosphate, or Universit y of Glasgow, and t hen recent ly ATP. When cells need energy, they use respiration to finished a post doc at t he Universit y of
construct molecules of ATP; they then break down the Hawaii.
2/8 webtopdfconverter.com ATP to fuel their metabolic reactions. Respiration comes In my spare t ime, I moonlight as a science in two forms. Normal cells, under normal conditions, communicat or, by making science more accessible t o t he public. I do t his by de- underg o aerobic respiration, which is a metabolic jargoning research papers and debunking pathway that requires oxygen. Here cells break down sensat ionalised science report ing in t he glucose into pyruvate, to eventually form ATP, while media. Jargonwall is my home for all my releasing carbon dioxide as a waste product. The oxygen science out reach effort s. needed is obtained from the air we breathe, diffuses into our blood and is then transported across all our tissues and organs. When there isn’t enough oxygen, cells switch TAGS to a different type of respiration: anaerobic respiration. Fluorescence Evolution T umour Quorum During anaerobic respiration, cells break down glucose Sensing cit izen science Molecular Biology into pyruvate and construct ATP, but produce lactic acid Apoptosis Medicine St em Cells instead of carbon dioxide. Aerobic respiration produces far Mutations Chemotherapy Immune more ATP than anaerobic respiration does; 32 molecules Syst em Scientists STEM Women of ATP from aerobic respiration vs a mere 2 molecules of Colour parasit ology Weird Nat ure ATP from anaerobic respiration, per molecule of glucose. Senescence Biofilm ST EM Social Media Science Communication academia Health Bacteria Genomics Engagement Personal Genetics Microbiology Cancer Stem Cells Virology Epidemiology Mentoring Cancer Open Access DNA HOA Hallmarks of Cancer Cell Signalling Mating Strategies RNA Int erference Neuroscience Evo-Devo In cancer cells undergoing aerobic glycolysis (pink pathway), glucose gets publishing Soapbox Cancer Research broken down into pyruvate and then lactic acid, producing only two molecules Google T ranscript ion Fact ors Debunking
of ATP. In cells undergoing normal respiration (orange pathway), glucose gets
completely broken down into pyruvate, which is further processed into carbon RECENT POSTS dioxide, producing 32 molecules of ATP. (Image credit: Buddhini Samarasinghe) Malignant Melanoma: Drug Resist ance is Fut ile
Aerobic Glycolysis T ranslat ion
Glycolysis is the process in which cells break glucose T ranscript ion
down into pyruvate, the first step in constructing the
DNA Replicat ion energy transfer molecule ATP. One of the main observations of the metabolism of cancer cells is that Blind Spot s: Seeing sexism in ST EM they display an enhanced rate of glycolysis during periods of fast growth. This phenomenon is known as the Warburg Ef f ect, after its discoverer Otto Warburg, and CATEGORIES is also known (somewhat confusingly) as aerobic Cat egories glycolysis. Cancer cells consume more than 20 times as Select Category much glucose compared to normal cells, but secrete lactic 3/8 webtopdfconverter.com acid instead of breaking it down completely into carbon dio xide. Why do cancer cells choose this inefficient ARCHIVES
metabolic pathway, when they can obtain sixteen times Archives
as much ATP per molecule of glucose by opting for normal Select Month
respiration?
The answer is twofold; first, although cancer cells STEM WOMEN
produce far less ATP per molecule of glucose, they produce it much faster. Cancer cells produce ATP almost a hundred times faster than normal cells. It is essentially a cost-benefit calculation, where the benefits of speedy ATP production outweigh the costs associated with inefficient glucose breakdown. Second, it is not just about ATP production. Cancer cells undergoing aerobic glycolysis also produce many intermediate biosynthetic precursors. These molecules are used as building blocks for the production of proteins, lipids and DNA required by the rapidly dividing cells. I creat ed ST EM Women, an init iat ive t o Greedy for Glucose support and promot e t he careers of women who work in ST EM fields. T oget her How do cancer cells satisfy their voracious appetite for wit h t wo ot her scient ist s, we encourage
glucose? Glucose typically enters cells through protein more women t o pursue ST EM careers and discuss t he challenges we face t owards channels known as glucose transporters. These act as achieving gender equalit y in ST EM. gateways through the surface of the cell membrane, selectively allowing glucose molecules to enter the cell. Cancer cells express increased amounts of glucose transporters on their cell surface membranes, so more glucose is brought inside the cell. Once inside the cell, the glucose is broken down by aerobic glycolysis into lactic acid, in order to speedily produce ATP and metabolic precursors through various metabolic pathways. These pathways are tightly controlled, requiring specific enzymes for processing the molecules from each step to the next. Cancer cells are addicted to these metabolic precursors; the enzymes that control these pathways are often over-expressed or mutated in cancer cells. This addiction is exploited in chemotherapy strategies. For example, 5-fluorouracil, methotrexate, and pemetrexed inhibit the biosynthesis of DNA precursor molecules. The high glucose consumption of cancer cells is also exploited when imaging cancer; Positron Emission Tomography (PET) combined with Computer Tomography (PET/CT) is used to detect the absorption of the glucose analogue fluorodeoxyglucose (FDG) by tumours, and has a better 4/8 webtopdfconverter.com than 90% sensitivity and specificity for the detection of metastases of most cancers.
Cancer cells consume more glucose than normal cells. This is exploited when imaging cancer. Positron Emission Tomography (PET) combined with Computer Tomography (PET/CT) is used to detect the absorption of the glucose analogue fluorodeoxyglucose (FDG) by tumours. In this image, besides the normal accumulation of the FDG molecule in the heart, bladder, kidneys, and brain, liver metastases of a colorectal tumour are visible in the abdominal region. Image credit: Jens Maus, Wikimedia Public Domain.
What is the utility of this alternative metabolic pathway
to healthy cells? The ability to grow and divide rapidly is useful in the context of wound healing and immune responses. When an immune response is required, immune cells massively increase their glucose uptake, switch from metabolising glucose through normal respiration to aerobic glycolysis, and switch on the multitude of enzymes that control the biosynthesis of proteins, lipids, and DNA. Therefore there is a strong evolutionary basis for rapid cell division and faster growth, despite the inefficient use of glucose in the process. Cancer cells hijack this metabolic switch in order to fuel their own uncontrolled growth.
The Mechanisms of a Metabolic Switch We therefore know why cancer cells opt to switch from normal respiration to aerobic glycolysis; the next question is how they do this. This is an active area of research; we are still deciphering the exact mechanisms of this metabolic switch. In a previous article, I explained how tumours often develop regions of low oxygen. This activates the hypoxia stress response, mediated by the hypoxia inducible f actor (HIF). However, over recent years it has become clear that HIF activity is not merely a response to low oxygen levels. HIF can be activated in response to a variety of triggers, such as radiation induced DNA damage, signalling from other proteins, growth factors, and the presence of pyruvate. Once activated, HIF can go on to activate genes that support aerobic glycolysis, and repress genes involved
5/8 webtopdfconverter.com in normal respiration.
HIF clearly plays a central regulatory role in switching the
metabolism of cancer cells from normal respiration to aerobic glycolysis. But what are the other signalling pathways that support this metabolic switch? One of the most important pathways is controlled by an enzyme known as Phosphoinositide 3 Kinase (often shortened to PI3K). PI3K can be activated by a variety of survival signals from outside the cell, via receptors on the cell surface membrane. Once activated, the PI3K pathway can mediate cell growth and survival, inhibit apoptosis, activate angiogenesis, and, notably here, activate aerobic glycolysis. In other words, activation of the PI3K pathway supports cancer cells. PI3K activates another protein known as AKT, which then activates the protein mTOR. Once activated, mTOR can also activate HIF, further supporting HIF’s efforts to switch cancer cell metabolism from normal respiration to aerobic glycolysis. PI3K signalling is negatively regulated by another protein known as PTEN. It is therefore unsurprising that cancers often have mutations that inactivate PTEN, thus preventing it from inactivating PI3K signalling.
It is
Switching metabolism in cancer. Growth or survival
factor signaling activates the PI3K signaling pathway. Activated PI3K activates AKT, which then activates 6/8 webtopdfconverter.com mTOR, which then activates HIF. HIF moves into the nucleus of the cell and activates genes that promote aerobic glycolysis while repressing normal metabolism. Activated PI3K can be attenuated by tumour suppressor protein PTEN. (Image credit: Buddhini Samarasinghe)
increasingly important to understand that this is not so
much a signalling pathway as it is a signalling web. Throughout this series, I have described normal cellular processes that serve to check uncontrolled growth and division. Many of the signalling pathways involved in these processes can cross-talk with each other: the components of one pathway can regulate another. For example, I discussed how the protein P53 is known as the Guardian of the Genome, as it is responsible for detecting and mitigating DNA damage. Another recently discovered function of P53 is in promoting normal respiration while dampening aerobic glycolysis. Given that P53 is the most commonly mutated protein in all cancers, it is unsurprising that the loss of normal P53 function disrupts this balance and pushes the cell towards aerobic glycolysis. The cellular pathways described in the Hallmarks of Cancer are not isolated; when mutated, they feed into each other, amplifying their effects and driving cells towards the uncontrolled growth that results in cancer.
It is also important to understand that cancer cells do not
function in isolation. Tumours are complex tissues, made up not only of cancer cells, but blood vessels, immune cells and other bystanders. These healthy cells are co-opted and subverted to perform tasks that support cancer progression. For example, the lactic acid secreted by cancer cells can induce tumour associated macrophages to create new blood vessels for the growing tumour, via the HIF pathway. The cellular pathways described in the Hallmarks of Cancer are not only interconnected, the body’s own cells, when trapped inside the tumour microenvironment, engage in complementary metabolic pathways, supporting and encouraging cancer cell survival and growth.
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