It was the great German doctor and Nobel laureate Otto Warburg who, back in 1921, discovered that cancer cells don’t use sugar as fuel the way we thought they would. Rather than “burning” sugar using oxygen like 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 in conditions where oxygen is available. However, it is not the most effective way to tap into all of the energy stored within sugar molecules and therefore left scientists intrigued for many years as to why cancer cells do this. 

Many proposed 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 within cells where sugar is “burned” and turned into energy very effectively. However, the hypothesis has not stood the test of time, as it was found that the mitochondria within cancer cells work as they should, and hence it could not have been the reason why cancer cells prefer the fermentation route to acquire 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 comes down to an important growth factor signaling molecule called PI3 kinase, an enzyme involved in a wide range of cellular activities such as cellular division, proliferation, growth, and survival.

“PI3 kinase is a key signaling molecule that functions almost like a commander-in-chief of cell metabolism,” Dr Li said in a statement. “Most of the energy-costly cellular events in cells, including cell division, occur only when PI3 kinase gives the cue.”

PI3 kinase has been extensively studied as part of a key signaling pathway involved in proliferation and cancer metabolism. As cancer cells start to shift and use the Warburg effect, the levels of PI3 kinase increases within the cells. This in turn, via a cascade of downstream events, leads to the cells becoming more committed to dividing. 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,” Dr Li says. “It’s what sends the growth signal for cancer cells to divide, and is one of the most overly active signaling pathways in cancer.”

To study this, researchers turned to another cell type in our bodies that has the ability to use the “ineffective” Warburg effect to investigate this phenomenon: immune cells. When certain types of T-cells are alerted of a nearby infection and need to rapidly divide to increase in number, they too are capable of turning off the sugar “burning” method of energy production, and turn on the Warburg effect to produce ATP and aid their proliferation. 

As the authors explain in the press release, this “switch” from using oxygen to starting to use 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. By using mice that lack the LDHA enzyme, the researchers found that animals could not maintain their normal levels of PI3 kinase within their T-cells, and were unable to fight off infections, because the T-cells didn’t divide properly as the PI3 kinase levels were not what it should be. 

This cemented the idea that the metabolic LDHA enzyme was somehow regulating the cells’ PI3 kinase signaling molecule. 

“The field has worked under the assumption that metabolism is secondary to growth factor signaling,” Dr Li says. “In other words, growth factor signaling drives metabolism, and metabolism supports cell growth and proliferation. So the observation that a metabolic enzyme like LDHA could impact growth factor signaling through PI3 kinase really caught our attention.”

The researchers go on to explain that like most enzymes, PI3 kinase uses ATP as an activating source of energy to perform its functions, like enforcing cellular division. As the Warburg effect ultimately results in ATP production, a positive feedback loop is established between the two molecules where ATP drives the activity of PI3 kinase, and with more PI3 kinase available, it results in rapid cell division and growth.

The findings challenge the accepted textbook view that cell signaling drives metabolism in cancer, as the researchers demonstrate in immune cells that use the Warburg effect, metabolic enzymes could be driving signaling molecules which in turn drives cellular division and growth, explaining a long-standing mystery as to why cancer cells might preferentially use the fermentation process to their advantage.

Although more research needs to be done using cancer cells instead of immune cells to test this, the current findings 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 commonly focused on PI3 kinase signaling enzyme.