It was the great German physician and Nobel winner Otto Warburg who, in 1921, discovered that cancer cells do not use sugar as fuel in the way we thought they would. Instead of “burning” sugar using oxygen, as most cells in our body prefer, cancer cells adopt a tactic known to be used by yeast cells: fermentation.
This specialized fermentation process (known as the Warburg effect) is fast and preferred by cancer cells to produce ATP (used by cells for energy), even in conditions where oxygen is available. However, it is not the most effective way to harness all the energy stored in the sugar molecules and therefore has left scientists puzzled for many years about why cancer cells do this.
Many proposed ideas have emerged over the years, since Warburg coined the term. One hypothesis was that cancer cells have defective mitochondria (the cell’s driving force), the organelle inside cells where sugar is “burned” and turned into energy very effectively. However, the hypothesis has not stood the test of time, as it has been found that the mitochondria within cancer cells function as they should, and therefore it cannot have been the reason why cancer cells prefer the fermentation route to acquire energy from the sugar.
Now researchers at the Sloan Kettering Institute led by Dr. Ming Li have published a potential explanation in the journal Science. Using biochemical and genetic experiments, the researchers showed that it all comes down to an important growth factor signaling molecule called PI3 kinase, an enzyme involved in a wide range of cellular activities, such as cell division, proliferation, growth and survival.
“PI3 kinase is a key signaling molecule that functions almost like a chief commander of cell metabolism,” said Li in a statement. “Most cellular events with high energy costs in cells, including cell division, occur only when PI3 kinase gives the clue.”
PI3 kinase has been widely studied as part of a key signaling pathway involved in cancer proliferation and metabolism. As cancer cells begin to change and use the Warburg effect, PI3 kinase levels increase within the cells. This, in turn, through a cascade of downstream events, leads cells to become more committed to division. Of course, this is a hallmark of cancer: rapid division and proliferation.
“PI3 kinase is a very, very critical kinase in the context of cancer,” says Dr. Li. “It is what sends the growth signal to cancer cells to divide and is one of the most active signaling pathways for cancer” .
To study this, researchers turned to another type of cell in our bodies that has the ability to use the “ineffective” Warburg effect to investigate this phenomenon: the cells of the immune system. When certain types of T cells are alerted to an upcoming infection and need to divide quickly to increase in number, they are also able to turn off the “burning” method of producing energy and activate the Warburg effect to produce ATP and help their proliferation.
As the authors explain in the press release, this “shift” from the use of oxygen to the beginning of the use of the fermentation process is controlled by an enzyme called lactate dehydrogenase A (LDHA). In turn, LDHA is regulated by the amount of PI3 kinase activity within the cell. When using mice without the LDHA enzyme, the researchers found that the animals were unable to maintain their normal levels of PI3 kinase within their T cells and were unable to fight infections, because T cells did not divide properly as PI3 kinase levels did not. they were what they should be.
This cemented the idea that the metabolic enzyme LDHA was somehow regulating the cell’s PI3 kinase signaling molecule.
“The field worked on the assumption that metabolism is secondary to growth factor signaling,” says Dr. Li. “In other words, growth factor signaling boosts metabolism and metabolism supports growth and proliferation cell phone. Therefore, the observation that a metabolic enzyme such as LDHA could impact growth factor signaling through PI3 kinase really caught our attention. “
The researchers explain that, like most enzymes, PI3 kinase uses ATP as a source of energy activation to perform its functions, such as strengthening cell division. As the Warburg effect finally results in the production of ATP, a positive feedback loop is established between the two molecules where ATP directs PI3 kinase activity and, with more PI3 kinase available, results in rapid cell division and growth.
The findings challenge the accepted book view that cell signaling boosts metabolism in cancer, as researchers demonstrate in immune cells that use the Warburg effect, metabolic enzymes may be boosting signaling molecules that in turn boost division and growth explaining an ancient mystery as to why cancer cells may prefer to use the fermentation process to their advantage.
While more research needs to be done using cancer cells instead of immune cells to test this, current findings open an exciting therapeutic path in the future, where someone may be able to direct cancer growth and proliferation towards LDHA, rather than the focused on the PI3 kinase signaling enzyme.