Sloan Kettering Institute specialists offer news answer to 100-year-old malignancy secret

Overview

• Post By : Kumar Jeetendra


• Source: Memorial Sloan Kettering Cancer Center


• Date: 23 Jan,2021

The year 2021 marks the 100th anniversary of a basic discovery that is taught in every biochemistry textbook. In 1921, German doctor Otto Warburg observed that cancer cells harvest energy from sugar sugar in a strangely inefficient manner: instead of”burn” it using cancer cells do what yeast do — they ferment it. This oxygen-independent process occurs quickly, but leaves a lot of the energy in glucose untapped.

Various hypotheses to describe the Warburg effect have been suggested over time, including the idea that cancer cells have defective mitochondria — their”energy factories” — and therefore cannot perform the controlled burning of glucose. (Cancer cells’ mitochondria work just fine, for example.)

Now a research team at the Sloan Kettering Institute led by immunologist Ming Li offers a new response, based on a hefty set of biochemical and genetic experiments and published January 21 in the journal Science.

It comes down to a previously unappreciated connection between Warburg metabolism and the activity of a powerhouse receptor from the cell called PI3 kinase.

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

Dr. Ming Li, Immunologist, Sloan Kettering Institute

As cells change to Warburg metabolism, the activity of PI3 kinase is raised, and subsequently, the cells’ devotion to split is strengthened. It’s a bit like giving the commander-in-chief a megaphone.

The findings revise the commonly accepted view among biochemists that sees metabolism as secondary to cell signaling. They also indicate that targeting metabolism could be an effective way to thwart cancer development.

Dr. Li and his team, including graduate student Ke Xu, studied Warburg metabolism in immune cells, which also rely on this seemingly inefficient form of metabolism. When immune cells have been alerted to the existence of an infection, a certain type called T cells change from the typical oxygen-burning kind of metabolism to Warburg metabolism as they grow in number and creep up infection-fighting machinery.

The key switch that regulates this change is an enzyme called lactate dehydrogenase A (LDHA), which is created in response to PI3 kinase signaling. As a result of this change, glucose stays only partly broken down and the cell’s energy currency, called ATP, is quickly generated in the cell’s cytosol. (In contrast, when cells use oxygen to burn glucose, the partially broken down molecules travel to the mitochondria and are further broken down there to make ATP on a delay.)

Dr. Li and his group found that in mice, T cells lacking LDHA couldn’t sustain their PI3 kinase activity, and as a result could not effectively fight infections. To Dr. Li and his team, this implied that this metabolic enzyme was controlling a cell’s signaling activity.

“The area has worked under the assumption that metabolism is secondary to growth factor signaling,” Dr. Li says.

As with other kinases, PI3 kinase is based on ATP to perform its work. Since ATP is the net product of Warburg metabolism, a positive feedback loop is set up between Warburg metabolism and PI3 kinase activity, securing PI3 kinase’s continued activity — and consequently cell division.

As for why activated immune cells would preferentially resort to this form of metabolism, Dr. Li suspects it has to do with the cells’ need to create ATP fast to ramp up their mobile division and infection-fighting machinery. The positive feedback loop ensures that after this program is engaged, it will be sustained until the infection is eradicated.

The cancer link
Though the team made their discoveries in immune cells, there are clear parallels to cancer.

“It is what sends the growth signal for cancer cells to divide, and is among the most overly active signaling pathways in cancer.”

Much like immune cells, cancer cells can use Warburg metabolism as a means to prolong the activity of this signaling pathway and therefore ensure their continued growth and division. The results raise the intriguing possibility that doctors could curb cancer growth by blocking the activity of LDHA — the Warburg”switch.”