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
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’
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
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.
over from the more efficient energy generating OxPhos to a less efficient
process, even though oxygen is freely available.
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.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^posted by JK on Fung's blog
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 I think it is a valuable piece in understanding cancer, along with
the work by Thomas Seyfried. Comments
appreciated -- firstname.lastname@example.org.
Back to researching and writing on the mechanism as to why we
get cancer and the other conditions associated with the high fructose western
diet. Dr. Fung, thanks for your insights
and confirmation that I had come to the right conclusions. Cancer is exceedingly
rare among native
population on a low sugar diet—see Taubes, Good Calories Bad Calories chapter
5, and Burkitt and Trowell’s 1981 book—available on line in Google books.