November 14th, 2010
(written by lawrence, however indented passages are often quotes)
My dad died of cancer 3 years ago and I’ve become fascinated with cancer research ever since. My own read on this literature has had me speculating about some metabolic links between diabetes and cancer – perhaps they spring from similar mechanisms? In that light, I found this article interesting, and was left wondering, what if cancer is only PKM2 funneling sugar into excess PEP? What if everything else that researchers have associated with cancer is merely incidental (the lack of the p53 gene, for instance) whereas the lack of PKM1 is really the main event? While the genes clearly shape the metabolism, this is a 2 way street – the metabolism also shapes the genes. Genetic code is not exactly like the software code that shapes a computer program – accidents of history can switch off whole sections of one’s genetic code. It is known that in mice who live with severely restricted diets (70% of satiation) suffer less cancer. Since the 70s its been common to assume that cancer arises from the genes, but what if the cancer causing genes “arise” from events that are metabolic?
Most human cells burn a six-carbon sugar called glucose. Through a long chain of reactions that require oxygen, the cells extract energy from the sugar and store it in molecular energy packets known as ATP. Cells use ATP to power a variety of functions, such as transporting molecules in and out of the cell, contracting muscle fibers and maintaining cell structure.
Glucose metabolism normally occurs in two stages, the first of which is known as glycolysis. It has been known for decades that cancer cells perform gylcolysis only, skipping the second stage, which is where most of the ATP is generated.
Vander Heiden’s new study focuses on glycolysis, traditionally thought to be a linear, nine-step process by which a cell turns one molecule of glucose into two molecules of pyruvate, an organic compound with three carbon atoms. That pyruvate is usually fed into the second phase of glucose metabolism.
“Everyone takes it for granted that this is how it works,” says Vander Heiden, who did this research as a postdoctoral fellow in the lab of Harvard Medical School Professor Lewis Cantley, senior author of the paper. But the new study shows that “there is another way it can work, and this other way seems to be at play in proliferating cells.” That could include rapidly dividing embryonic cells as well as cancer cells.
Scientists already knew that cancer cells replace one type of a key metabolic enzyme known as pyruvate kinase with another. Both versions of the enzyme (PKM1 and PKM2) catalyze the very last step of glycolysis, which is the transformation of a compound called PEP to the final product, pyruvate.
In the new study, the researchers found that PEP is involved in a previously unknown feedback loop that bypasses the final step of glycolysis. In cancer cells, PKM2 is not very active, causing PEP to accumulate. That excess PEP activates an enzyme called PGAM, which catalyzes an earlier step in glycolysis. When PGAM receives that extra boost, it produces even more PEP, creating a positive feedback loop in which the more PEP a cell has, the more it makes.
The most important result of this loop is that the cell generates a large pool of another chemical that is formed during an intermediate step of the reaction chain. Vander Heiden believes this compound, called 3-phosphoglycerate, is diverted into synthetic pathways such as the production of DNA, which can become part of a new cancer cell. In future studies, he plans to investigate how that diversion occurs.
Jeffrey Rathmell, associate professor of cancer biology at Duke University Medical Center, says the discovery of this bypass pathway explains the apparent paradox of why cancer cells have an overactive metabolism even though PKM2 is much less active than the normal PKM1 form of the enzyme.