The Warburg Effect – Cancer 14

The Warburg Effect refers to the fact that cancer cells, somewhat counter intuitively, prefers fermentation as a source of energy rather than the more efficient mitochondrial pathway of oxidative phosphorylation (OxPhos). We discussed this in our previous post.

In normal tissues, cell may either use OxPhos which generates 36 ATP or anaerobic glycolysis which gives you 2 ATP. Anaerobic means ‘without oxygen’ and glycolysis means ‘burning of glucose’. For the same 1 glucose molecule, you can get 18 times more energy using oxygen in the mitochondrion compared to anaerobic glycolysis. Normal tissues only use this less efficient pathway in the absence of oxygen – eg. muscles during sprinting. This creates lactic acid which causes the ‘muscle burn’.

However, cancer is different. Even in the presence of oxygen (hence aerobic as opposed to anaerobic), it uses a less efficient method of energy generation (glycolysis, not phosphorylation). This is found in virtually all tumors, but why? Since oxygen is plentiful, it seems stupid, because it could get way more ATP using OxPhos. But it can’t be that stupid, because it happens in virtually every single cancer cell in history. This is such as striking finding that it has become one of the emerging ‘Hallmarks of Cancer’ as detailed previously. But why? When something seems stupid, but happens anyways, it’s usually us who are stupid for not understanding. So we need to try to understand it rather than dismissing it as a freak of nature.

For single celled organisms like bacteria, there is evolutionary pressure to reproduce and grow as long as nutrients are available. Think of a yeast cell on a piece of bread. Grows like crazy. Yeast on a dry surface like a countertop stays dormant. There are two very important determinants of growth. You need not only the energy to grow, but also the raw building blocks. Think of a brink house. You need construction workers, but also bricks. Similarly, cells need the basic building blocks (nutrients) to grow.

For multi celled organisms, there is generally plenty of nutrients floating around. The liver cell, for example, finds lots of nutrients all over the place. The liver does not grow because it only takes up these nutrients when stimulated by growth factors. In our house analogy, there are plenty of bricks, but the foreman has told the construction workers not to build. So nothing is built.

One theory is that perhaps the cancer cell is using the Warburg Effect to not just generate energy, but also the substrate needed to grow. For a cancer cell to divide, it needs lots of cellular components, which requires building blocks like Acetyl-Co-A, which can be made into other tissues like amino acids and lipids.

For example, palmitate, a major constituent of the cell wall requires 7 ATP of energy, but also 16 carbons that can come from 8 Acetyl-CoA. OxPhos provides lots of ATP, but not much Acetyl-CoA because it is all burned to energy. So, if you burn all the glucose to energy, there is no building blocks with which to build new cells. For the palmitate, 1 glucose molecule will provide 5 times the energy needed, but will need 7 glucose to generate the building blocks. So, for a proliferating cancer cell, generating pure energy is not great for growth. Instead, aerobic glycolysis, which produces both energy and substrate will maximize the rates of growth and proliferate the fastest.

This may be important in an isolated environment, but cancer does not arise in a petri dish. Instead nutrients are rarely a limiting factor in the human body – there is plenty of glucose and amino acids everywhere. There’s lots of available energy and building blocks so there is no selective pressure to maximize ATP yield. Cancer cells perhaps use some glucose for energy and some for biomass to support expansion. In an isolated system, it may make sense to use some resources for bricks and some for construction workers. However, the body is not such a system. The burgeoning breast cancer cell, for example, with access to the blood stream, which has both glucose for energy and amino acids and fat for building cells.

It also does not make any sense of the link with obesity, where there are plenty of building blocks around. In this situation, cancer should maximize glucose for energy, since it can easily obtain building blocks. Thus, it is debatable whether this explanation of the Warburg Effect plays any role in cancer’s origin.

There is an interesting corollary, however. What if nutrient stores were significantly depleted? That is, if we are able to activate our nutrient sensors to signal ‘low energy’ then the cell would face selective pressure to maximize energy production (ATP) moving away from cancer’s preferred aerobic glycolysis. If we lower insulin and mTOR, while increasing AMPK. There is a simple dietary manipulation that does this – fasting. Ketogenic diets, while lowering insulin, will still activate the other nutrient sensors mTOR and AMPK.

Glutamine

Another misconception of the Warburg Effect is that cancer cells can only use glucose. This is not true. There are two main molecules that can be catabolized by mammalian cell – glucose, but also the protein glutamine. Glucose metabolism is deranged in cancer, but so is glutamine metabolism. Glutamine is the most common amino acid in the blood and many cancers seem to be ‘addicted’ to glutamine for survival and proliferation.

The effect is most easily seen in the Positron Emission Tomography (PET) scan. PET scans are a form of imaging used heavily in oncology. A tracer is injected into the body. The classic PET scan used fluorine-18 fluorodeoxyglucose (FDG) which is a variant of regular glucose which is tagged with a radioactive tracer so it can be detected by the PET scanner.

Most cells take up glucose at a relatively low basal rate. However, cancer cells drink up the glucose like a camel drinks up water after a desert trek. These tagged glucose cells accumulate in the cancerous tissue and can be seen as active sites of cancer growth.

In this example of lung cancer, there is a large area in the lung that is drinking up the glucose like crazy. This demonstrates that cancer cells are far, far more glucose avid than regular tissues. However, there is another way to do the PET scan, and that is to use the radioactively tagged amino acid glutamine. What this demonstrates is that some cancer are just as avid for glutamine. Indeed, some cancers cannot survive without glutamine and seem ‘addicted’ to it.

Where Warburg made his seminal observations about cancer cells and perverted glucose metabolism in the 1930s, it was not until 1955 that Harry Eagle noted that some cells in culture consumed glutamine by over 10 times that of other amino acids. Later studies in the 1970s showed that this was true for many cancer cell lines also. Further studies showed that the glutamine was being converted to lactate, which seems rather wasteful. Instead of burning it as energy, the glutamine was being changed to lactate, seemingly a waste product. This was the same ‘wasteful’ process seen in the glucose. Cancer was changing glucose to lactate and not getting the full energy bonanza from each molecule. Glucose provides the mitochondria with a source of acetyl-CoA and glutamine provides a pool of oxaloacetate (see diagram). This supplies the carbon needed to maintain citrate production in the first step of the TCA cycle.

Certain cancers seem to have exquisite sensitivity to glutamine starvation. In vitro, pancreatic cancer, glioblastoma multiform, acute myelogenous leukaemia for example ofter die off in the absence of glutamine. The simplistic notion that a ketogenic diet may ‘starve’ the cancer of glucose does not hold up to the facts. Indeed, in certain cancers, glutamine is the more important component.

What’s so special about glutamine? One of the important observations is that mTOR complex 1, mTORC1 a master regulator of protein production is responsive to glutamine levels. In the presence of sufficient amino acids, growth factor signalling occurs through the insulin-like growth factor (IGF)-PI3K-Akt pathway.

This PI3K signalling pathway is critical for both growth control and glucose metabolism, underscoring once again the close relationship between growth and nutrient/ energy availability. Cells do not want to grow unless nutrients are available.

We see this in the study of oncogenes, most of which control for enzymes called tyrosine kinases. One common feature of tyrosine kinase signaling associated with cell proliferation is regulation of glucose metabolism. This does not happen in normal cells that are not proliferating. The common MYC oncogene is particularly sensitive to glutamine withdrawal.

So, here’s what we know. Cancer cells:

  1. Switch over from the more efficient energy generating OxPhos to a less efficient process, even though oxygen is freely available.
  2. Need glucose, but also need glutamine.

But the million dollar question still remains. Why? It is too universal to be just a fluke. It’s also not simply a dietary disease, since many things, including viruses, ionizing radiation and chemical carcinogens (smoking, asbestos) cause cancer. If it is not simply a dietary disease, then a purely dietary solution does not exist. The hypothesis that makes the most sense to me is this. The cancer cell does not use the more efficient pathway, because it can’t. If the mitochondrion are damaged or senescent (old), then cells will naturally look for other pathways. This drives cells to adopt a phylogenetically ancient pathway of aerobic glycolysis in order to survive. Now, we come to the atavistic theories of cancer.

 

Start here with Cancer Part 1

Continue to Cancer Part 15 – Beyond the Somatic Mutation Theory of Cancer

2018-04-25T17:04:04+00:00 47 Comments

About the Author:

Dr. Fung is a Toronto based kidney specialist, having graduated from the University of Toronto and finishing his medical specialty at the University of California, Los Angeles in 2001. He is the author of the bestsellers ‘The Obesity Code’ and ‘The Complete Guide to Fasting’. He has pioneered the use of therapeutic fasting for weight loss and type 2 diabetes reversal in his IDM clinic.

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Curtis
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Curtis

Isn’t it anaerobic glycolysis?

linas
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linas

that was my exact reaction! but then after re-reading the first couple paragraphs several times….. I realized I mis interpreted and Dr. was right

John Kellett
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John Kellett

My understanding is that glycolysis is always anaerobic. Glycolysis is the process of conversion of 1 molecule of glucose to 2 molecules of pyruvate. This series of reactions occurs in the cytoplasm in the absence of oxygen and is therefore, by definition anaerobic. Therefore, the term aerobic glycolysis is meaningless. What determines whether the whole energy creating process is aerobic or anaerobic is what happens after glycolysis. In humans with mild “aerobic” activity, all the pyruvate created by glycolysis can pass into the mitochondria where it can be comfortably managed by the electron transport chain, using oxygen, to create ATP… Read more »

Curtis
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Curtis

That was my understanding as well; I understood that cancer cells generally exist in a low o2 environment

John Kellett
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John Kellett

Correction. The 2ATP molecules created from glycolysis are created anaerobically in the cytoplasm. In actuality, 4 ATP molecules are created per glucose but 2 ATP are used during the early stages of glycolysis leaving net 2 molecules of ATP/ glucose molecule.
The NADH (not NADH2) are transported to the mitochondria where they create further ATP aerobically.

Curtis
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Curtis

I did go back and re-read some of the Thomas Seyfried stuff and he does say Aerobic Glycolysis… so the doc is correct, I stand corrected

John Kellett
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John Kellett

I still maintain that the process of glycolysis itself is anaerobic because there is no oxygen involved at this cytoplasmic stage if one follows the series of 10 reactions involved in glycolysis, I think that when people refer to aerobic and anaerobic glycolysis they are a short-hand way of referring to the availability of oxygen for the whole energy creating process which means glycolysis and the subsequent processes of Kreb’s cycle and the electron transport chain and/or fermentation. When overall conditions are aerobic, pyruvate is drawn into the Kreb’s cycle/ETC phase ie the aerobic phase. When oxygen is unavailable or… Read more »

Oscar Zepeda
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Jason Fung is An Absolute Genius !!!!!!

Norac
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Norac

Hello Dr. Fung,
Terrific series on cancer – I can’t wait from one week to the next to read more.
But…after the instances mentionend in the two first paragraphs, shoudn’t we read “anaerobic glycolysis” instead of “aerobic glycolysis”?

boris
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boris

what a weird naming convention, aerobic glycolysis make you think that the oxygen is being used, but in case of cancer cells it is not but it’s still called aerobic…

should be called anaerobic glycolysis with presence of oxygen? lol

Hap
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Hap

Yes…cancer cells might prefer fermentation to divert carbon to other “growth ” processes as opposed to be use soley for ATP generation. In addition, although anaerobic glycolysis “ineffcient” (ie less ATP per molecule glucose) compare to aerobic…..the RATE of ATP synthesis in the cycle is much faster. Cancer does not really care about efficiency and if lots of substrate around, will prefer to produce ATP faster.

Jim
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Jim

Wonderful series on cancer. I look forward to each new segment. Thanks for what you do. You enable thousands to achieve better health. God bless.

Kathy McGraw
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Kathy McGraw

Love reading Dr. Fung!

Rob Bracken
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Rob Bracken

Can’t wait for the next installment of this “murder mystery.”

Bharath Raj Reddy M
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Bharath Raj Reddy M

The same was explained by Dr Ron Rose deal way back in 2011, below is the link.
http://drrosedale.com/blog/2011/11/18/cancer-pain-relief-diet-ron-rosedale-and-shelley-schlender/#axzz57oMJfqsn

Richard
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Richard

Dr. Fung: Excellent. Thank you.

Stephen P Ruis
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Stephen P Ruis

Re “This creates lactic acid which causes the ‘muscle burn’.” This has been shown to be not true. Lactic acid (a) doesn’t “burn” anything and actually extends the ability of the muscle to keep working.

Fascinating post by the way. This may lead to interesting treatment options.

April
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April

By “muscle burn” he means the burning pain the day after a workout. And in a previous post was explained exactly what you say… 😊

linas
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linas

so does this mean that fasting would do the trick, so to speak? lower insulin and mtor but raise ampk and thus prevent the cancer from growing?

Benthamite
Guest

Glad to see a college-level article. As stated before in a posting to your blog, the gene-turn-on and off theory fits Occam’s razor of simple and better than other theories, in this case cancer. I am attaching a link to my website, where I have pasted a seminal article (http://healthfully.org/rcdm/id1.html) on a macrophage turning on certain genes (or swapping them in a precancerous or tumor cell or indolent cancer cell to give it the properties of a macrophage and this makes that cell line and subsequent mutated cells of that line a deadly metastatic cancer. I tell you this because… Read more »

Pete Kaye
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Pete Kaye

As a layman, some of this is over my head, but I am always in awe of how Dr. Fung can get me to understand this biological stuff. Who would think the spark of learning could be so ignited in a 66 year old guy who was supposed to be dead 12 years ago?

sten bjorsell
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sten bjorsell

Looking fwd to next chapter indeed! Seems that a lot of good groundwork is being done! I did not know that glutamine is fermented and also produce lactate. Is lactate not only a byproduct and a food for cancer-growth, but also a necessary protection for cancer? I read that lactate is an antioxidant and also that some emergency cell communication takes place with ROS chemicals, oxidants, that would be quenched in an antioxidant “lactate cloud”. It would mean lactate could have a secondary effect of blockin signals to the immune system so that it will never know that anything is… Read more »

sten bjorsell
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sten bjorsell

I found that there are 3 natural “factors” that reduce lactate. Carnosine, phospate, and bicarbonate. Sportsmen thought that ingesting bicarbonate was “the thing” to increase stamina as it neautralizes lactate, and it works. But since it has been found that carnosine, that can be ingested and also naturally builds in muscles has the same effect, but much stronger! Hence it would also work to reduce lactate building up in cancer. At the same time there are researchers out here trying to find out why carnosine has an “antiproliferative effect” on cancer! It could also explain why a friend more or… Read more »

David A Haack
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David A Haack

sten, Your bringing up bicarbonate as one of 3 “factors” that reduce lactate confirms my assumption that the reason sodium bicarbonate has proved effective as a cancer treatment. My cousin was doing the “baking-soda protocol” during his two-year ordeal with chemo and radiation to help save his kidneys from the ravages of such treatment. He was originally diagnosed with stage 4 prostate cancer back in Sep. ’15. Normally one has a much more limited outlook when faced with cancer in the bones and close to vital organs and tissues. He has confounded all by outliving his prognosis and surviving about… Read more »

Moni
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Moni

Oh, how sad… Check Dr. D’Agostino’s videos on YouTube. Or the Cancer Diet mentioned below by someone. No one should have to suffer so much. 🙁

steve b
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steve b

this stuff is hard to understand as a layman but glutamine was recommended for me to take as a supplement. After reading this, even though i dont have cancer, I am assuming i should not take it anymore? I have used this supplement as part of my regimen to lower my type 2 diabetes blood sugar to non diabetic levels in a short time.

JohnM
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JohnM

Paraphrasing from page 200-204 in the book Keto For Cancer it’s problematic to reduce glutamine because the body can create its own. Still, the author suggests reducing overall protein consumption, and specifically any supplements that have glutamine as an ingredient. Of course, these recommendations are targeted to those dealing with cancer so may not apply to others less challenged.

In support of your T2D goal, you might consider Dr Fung’s new book “The Diabetes Code” due out April 3rd:

https://www.amazon.com/Diabetes-Code-Prevent-Reverse-Naturally/dp/1771642653/ref=sr_1_3?s=books&ie=UTF8&qid=1519428319&sr=1-3

Kathryn
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Kathryn

Wow. Fantastic post. Knew about the glucose, but not the glutamine. Oh, yes, I see a slightly longer fast in my future. Agree with R Bracken, can’t wait for the next installment !

Erin
Guest
Erin

I have taken glutamine to heal my gut after antibiotic use, along with probiotics. In my initial fasting tryouts, I’m always stopped at about 36 hours with diarrhea. I tried taking glutamine while on the fast, and it prevents this reaction. So after reading this, I’ll get by without it, since it obviously limits any anti-cancer benefit from fasting by activating mTOR?

Doug Gardiner
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Doug Gardiner

The plot thickens. Will our hero, Fasterman, be able to conquer the confounding ways of the super villain? He may have met his match this time.

Katrina M Iannuzzi
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Katrina M Iannuzzi

Wowww!

janda
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janda

Mushrooms and seaweed for example and all the ‘Umami’ rich foods contain a lot of glutamine, most of those foods are known as ‘cancer fighting’foods,
i always find that difficult to understand Also,knowing that glutamine restriction as other amino acids extend life
So should one restrict those foods ?

charm
Guest
charm

thanks Dr. Fung.
I was going to start to take the supplement l-glutamine but now I am wondering if I might just feeding any cancers cells that may be wanting to grow.
Dr. Fung please provide more information about supplementing with glutamine.
thanks

Francoise zhembert
Guest
Francoise zhembert

Thank you Dr. Fung. You are a true teacher. You generously share you knowledge and use language that a lay person can understand. Some of it goes over my head, but I don’t let that stop me from learning.

Anais Starr
Guest

Very nice! I am loving this moving pathway of discovery. Look forward to the next article.

sten bjorsell
Guest
sten bjorsell

It seems some posts are vanishing and replies are only shown to us who wrote initial comments. Dr Fung, is your site being hacked? In reply to Dave Haack(!?): Try the carnosine or beta -alanine sublingual after dissolving in water. Sorry to leave it short, hopefully, your cousin gets this message.

David A Haack
Guest
David A Haack

Thank sten.

didy2
Member
didy2

What advice does dr.fung has for me who is undergoing chemo? Start the keto diet, fasting? Losing weight is my biggest enemy I was told, hence I won’t get any fasting guidance or support from my oncologists! What to do? I’m desperate, help! My appointment with dr.fung is not until July, when I have finished my treatments.

sten bjorsell
Guest
sten bjorsell

Get Valter Longo’s new book “The Longevity Diet”. It contains information about “Differential stress resistance” which means that ordinary cells reduce activity and fuel usage to a minimum during periods of little nutrition, like fasts, while cancer cells do not. Trials preceding chemo with 3-5 days fasting, or “fasting mimicking diet”, and 2-3 days after have shown increased Chemo effectiveness as ordinary cells are affected very little while cancer cells are damaged substantially. See my earlier posts here also. Find an oncologist that is willing to monitor your progress.

Moni
Guest
Moni

Read “The Cancer Diet (or keto for cancer?) book. It was recently published. And watch Dr. D’Agostino’s videos on YouTube. God bless you.

Guyfranke
Guest
Guyfranke

Dr. Fung, i think you’re onto something with that last statement you make … ‘If the mitochondrion are damaged or senescent (old), then cells will naturally look for other pathways. This drives cells to adopt a phylogenetically ancient pathway of aerobic glycolysis in order to survive.’

Thanks and CHeers !!

Trevor Campbell
Guest
Trevor Campbell

I think jason should read up about the “Reverse Warburg ”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593685/