Posted on 01/15/2021 12:49:54 PM PST by BenLurkin
In the 1920s, German chemist Otto Warburg discovered that cancer cells don’t metabolize sugar the same way that healthy cells usually do. Since then, scientists have tried to figure out why cancer cells use this alternative pathway, which is much less efficient.
MIT biologists have now found a possible answer to this longstanding question. In a study appearing in Molecular Cell, they showed that this metabolic pathway, known as fermentation, helps cells to regenerate large quantities of a molecule called NAD+, which they need to synthesize DNA and other important molecules. Their findings also account for why other types of rapidly proliferating cells, such as immune cells, switch over to fermentation.
“This has really been a hundred-year-old paradox that many people have tried to explain in different ways,” says Matthew Vander Heiden, an associate professor of biology at MIT and associate director of MIT’s Koch Institute for Integrative Cancer Research. “What we found is that under certain circumstances, cells need to do more of these electron transfer reactions, which require NAD+, in order to make molecules such as DNA.”
Vander Heiden is the senior author of the new study, and the lead authors are former MIT graduate student and postdoc Alba Luengo PhD ’18 and graduate student Zhaoqi Li.
Inefficient metabolism
Fermentation is one way that cells can convert the energy found in sugar to ATP, a chemical that cells use to store energy for all of their needs. However, mammalian cells usually break down sugar using a process called aerobic respiration, which yields much more ATP. Cells typically switch over to fermentation only when they don’t have enough oxygen available to perform aerobic respiration.
Since Warburg’s discovery, scientists have put forth many theories for why cancer cells switch to the inefficient fermentation pathway. Warburg originally proposed that cancer cells’ mitochondria, where aerobic respiration occurs, might be damaged, but this turned out not to be the case. Other explanations have focused on the possible benefits of producing ATP in a different way, but none of these theories have gained widespread support.
In this study, the MIT team decided to try to come up with a solution by asking what would happen if they suppressed cancer cells’ ability to perform fermentation. To do that, they treated the cells with a drug that forces them to divert a molecule called pyruvate from the fermentation pathway into the aerobic respiration pathway.
They saw, as others have previously shown, that blocking fermentation slows down cancer cells’ growth. Then, they tried to figure out how to restore the cells’ ability to proliferate, while still blocking fermentation. One approach they tried was to stimulate the cells to produce NAD+, a molecule that helps cells to dispose of the extra electrons that are stripped out when cells make molecules such as DNA and proteins.
When the researchers treated the cells with a drug that stimulates NAD+ production, they found that the cells started rapidly proliferating again, even though they still couldn’t perform fermentation. This led the researchers to theorize that when cells are growing rapidly, they need NAD+ more than they need ATP. During aerobic respiration, cells produce a great deal of ATP and some NAD+. If cells accumulate more ATP than they can use, respiration slows and production of NAD+ also slows.
“We hypothesized that when you make both NAD+ and ATP together, if you can't get rid of ATP, it's going to back up the whole system such that you also cannot make NAD+,” Li says.
Therefore, switching to a less efficient method of producing ATP, which allows the cells to generate more NAD+, actually helps them to grow faster. “If you step back and look at the pathways, what you realize is that fermentation allows you to generate NAD+ in an uncoupled way,” Luengo says.
Solving the paradox
The researchers tested this idea in other types of rapidly proliferating cells, including immune cells, and found that blocking fermentation but allowing alternative methods of NAD+ production enabled cells to continue rapidly dividing. They also observed the same phenomenon in nonmammalian cells such as yeast, which perform a different type of fermentation that produces ethanol.
“Not all proliferating cells have to do this,” Vander Heiden says. “It’s really only cells that are growing very fast. If cells are growing so fast that their demand to make stuff outstrips how much ATP they’re burning, that’s when they flip over into this type of metabolism. So, it solves, in my mind, many of the paradoxes that have existed.”
The findings suggest that drugs that force cancer cells to switch back to aerobic respiration instead of fermentation could offer a possible way to treat tumors. Drugs that inhibit NAD+ production could also have a beneficial effect, the researchers say.
The research was funded by the Ludwig Center for Molecular Oncology, the National Science Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, the Medical Research Council, NHS Blood and Transplant, the Novo Nordisk Foundation, the Knut and Alice Wallenberg Foundation, Stand Up 2 Cancer, the Lustgarten Foundation, and the MIT Center for Precision Cancer Medicine.
White guy science. It is racist I tell you!
Thanks for the post. I will definitely read this.
I have no idea what any of that means on a personal level
“I have no idea what any of that means on a personal level”
Better prospects for your kids.
Thanks for posting, BL. I never knew that “cancer cells don’t metabolize sugar the same way that healthy cells usually do,” that they use fermentation, and this has been known for 100 years. What a fascinating problem to solve.
“Better prospects for your kids.”
Great answer, TG. Spot-on.
Nad is bad
I understand none of this but have seen NAD being used as a possible treatment for COVID. Didn’t really read up on it to see if it had any validity
Here in S. FL there are quite a few Dr shops (real MDs) that have opened boutiques with drug/mineral/vitamin IV concoctions. One such treatment in NAD+ which is touted as a unique treatment and powerful. I can’t tell from this article if such a treatment would be arguably a benefit or a cancer fuel?
Sounds like a reasonable amount of vegetables is a good preventative approach, since many contain NAD inhibitors.
In biology, it’s called the krebs cycle. It’s the life and death of a cell and the changes that take place which is usually nothing more than giving up an atom or the electron that travels with it. When a teeny change happens, a new substance is formed, energy bursting forth or reduced.
It all happens in this orderly fashion which we were sposta memorize..but most of us didn’t.
This article describes the life cycle of a cancer cell compared to a normal healthy cell and provides the answer to developing drugs to inhibit the krebs cycle of a cancer cell while allowing healthy cells to continue a normal life cycle.
This is important because todays chemo is hard to ebdure. It affects all cells, and sometimes only acts as brakes on the cancer cells...the cancer returns, chemo again, and yiu get sicker and die.
If you ever get cancer...i hope you don’t, you will understand how the findings of these researchers, impact you.
Hope that helps!
I picked the enzyme Alcohol Dehydrogenase to do a research paper on. It was fascinating to read how "Competitive Inhibition" for this enzyme is how doctors save the lives of kids who ingest a fatal amount of ethylene glycol (ie antifreeze). The enzyme's purpose is to digest ethyl alcohol (ie booze) in your tissues by converting it to acetaldehyde (H3C-CH2OH + 1/2 O2 => H3C-COH + H2O). But it also happens to convert ethylene glycol (HOH2C-CH2OH) into a toxic substance by converting both "H2OH" groups at the ends of the 2-carbon chain. So the way to save the patient is to flood their blood stream with as much booze as you dare without the side effects killing them, and keep the level high for as long as is needed for the booze to "out-compete" the ethylene glycol for the "attention" of the enzyme, while meanwhile the kidneys slowly flush out the un-converted ethylene glycol.
I got a big chuckle out of an incident with the T.A. One day just as her office hours were ending and she was locking her door and mistakenly thought she was about to make a clean getaway, I showed up with a test or quiz paper in my hand to argue about what I considered a mis-grading. She sighed as she put the key back into to re-open her door and said to me: "Let me guess. You're a Pre-Med major, right?" I replied, "Nope! I'm a Math Major with a Comp Sci Option". You should have seen her jaw drop. Heh heh!
Fermentation converts sugar. This could explain why sugars and carbs “feed” cancer cells.
Is there a proven way to “starve” cancer cells?
Will severely limiting sources of glucose and carbs in your diet have any effect on Ca cell growth?
Is the hypothesis that ketosis inhibits Ca cell growth just that, or is it a provable theory now?
All cells are fed with sugars. Cancer cells are just ones that are growing fast yet don’t do their jobs. Kind of like democrats.
You kill them by disrupting their ability to multiply while causing cellular death.
The SAD (Standard American Diet) has WAY too much sugar. In the 1600s British death records began listing “by teeth”, a result of the sugar obtained by the slave trade. For a while black teeth were considered “fashionable” as only the wealthy could afford sugar.
I’d suggest a search on “keto cancer” or “low carb cancer.”
Normal cells can use either fat or sugar for fuel. Cancer cells can only use sugar. So if you eat a lot of sugar (or things that convert to sugar) you are providing lots of food for cancer cells to grow and multiply. If you limit sugar, you starve cancer cells, killing them or severely retarding their growth. Eat a low sugar, keto/meat diet with a good percentage of healthy fats. High fructose corn syrup makes cancer cells grow like crazy. Never eat it. Once your normal cells convert over to fat burning mode, you'll lose weight, have lots of even steady energy, and minimize your chance of getting cancer.
Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.