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It was the great German physician and Nobel Prize winner Otto Warburg who in 1921 discovered that cancer cells do not use sugar for fuel as we thought. Rather than “burning” the 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 rapid and preferred by cancer cells to produce ATP (used by cells for energy) even under conditions where oxygen is available. However, this is not the most efficient way to harness all of the energy stored in sugar molecules and therefore has left scientists for many years puzzled as to why cancer cells do this.
Many suggested ideas have surfaced over the years since Warburg coined the term. One hypothesis was that cancer cells have faulty mitochondria (the powerhouse of the cell), the organelle in cells where sugar is “burned” and turned into energy very efficiently. However, the hypothesis did not stand the test of time, as it was found that the mitochondria in cancer cells work as they should, and therefore, this could not be the reason why cells Cancer patients prefer the fermentation route to gain energy from 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 boiled 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 as a commander-in-chief of cell metabolism,” Dr. Li said in a statement. “Most energy-intensive cellular events in cells, including cell division, occur only when PI3 kinase gives the signal.”
PI3 kinase has been extensively studied as part of a key signaling pathway involved in cancer proliferation and metabolism. As cancer cells begin to move around and use the Warburg effect, the levels of PI3 kinase increase in the cells. This in turn, via a cascade of downstream events, leads the cells to engage more in division. This is of course a hallmark of cancer: rapid division and proliferation.
“PI3 kinase is a very, very critical kinase in the context of cancer,” says Dr. Li. “This is what sends the signal for the growth of cancer cells to divide, and this is one of the pathways. most active cancer signaling. “
To study this, the researchers turned to another type of cell in our body that has the ability to use the “ineffective” Warburg effect to study this phenomenon: immune cells. When certain types of T cells are alerted to a nearby infection and need to divide rapidly to increase in number, they are also able to turn off the sugar ‘burning’ energy production method and activate the Warburg effect to produce ATP and contribute to their proliferation.
As the authors explain in the press release, this “shift” from oxygen usage to the start 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 in the cell. Using mice lacking the LDHA enzyme, the researchers found that the animals could not maintain their normal levels of PI3 kinase in their T cells and were unable to fight off infections because the T cells did not divide properly into as long as PI3. the kinase levels weren’t where they should be.
This cemented the idea that the metabolic enzyme LDHA somehow regulated the PI3 kinase signaling molecule in cells.
“The field has operated under the assumption that metabolism is secondary to growth factor signaling,” says Dr. Li. “In other words, growth factor signaling stimulates metabolism and metabolism supports growth. and cell proliferation. So, the observation that a metabolic enzyme like LDHA could impact growth factor signaling via PI3 kinase really caught our attention.
The researchers go on to explain that, like most enzymes, PI3 kinase uses ATP as a source of activating energy to perform its functions, such as strengthening cell division. As the Warburg effect ultimately results in the production of ATP, a positive feedback loop is established between the two molecules where ATP drives PI3 kinase activity, and with more PI3 kinase available, the result is a rapid cell division and growth.
The findings challenge the popular view that cell signaling stimulates metabolism in cancer, as researchers demonstrate in immune cells that use the Warburg effect, metabolic enzymes could be the source of signaling molecules which in turn stimulate cell division and growth, explaining a long-standing mystery. why cancer cells might prefer to use the fermentation process to their advantage.
While more research is needed using cancer cells instead of immune cells to test this, the current results open up an exciting therapeutic avenue in the future where one might be able to target cancer growth and proliferation. by targeting LDHA, instead of the more common signaling enzyme-based PI3 kinase.
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