Enzyme found to both hinder and help cancer growth

Friday, 09 November, 2018

Enzyme found to both hinder and help cancer growth

Researchers at the Salk Institute for Biological Studies have solved a longstanding mystery surrounding the protein complex AMPK, long thought to suppress cancer by slowing cellular metabolism.

AMPK acts as a fuel gauge for the cell, overseeing energy input and output to keep the cell running smoothly. Similar to a car sensor flashing a low-petrol signal or turning off a vehicle’s AC to save energy, AMPK slows down cell growth and changes the cell’s metabolism if the cell’s fuel (nutrients) is low.

Previously, Salk’s Professor Reuben Shaw and his team discovered that AMPK could halt tumours’ revved-up metabolism, as well as restore normal function to the liver and other tissues in diabetics. But the Shaw lab’s latest work, published in the journal Cell Metabolism, suggests that AMPK actually helps large tumours grow, having observed groups of mice with and without the AMPK fuel gauge to see how tumours developed.

The team analysed which genes in tumour cells from the same mouse models were being activated under various conditions. One gene that was particularly active was Tfe3, which is known to activate cellular recycling. When tumours became large enough that cells in the middle were too far from easy access to nutrients, AMPK signalled Tfe3 to initiate recycling of cellular materials as nutrients — effectively cannibalising pieces of the cell — which the tumour can use to grow.

Genetically engineered lung tumors (solid purple) within the native lung environment. Image credit: Salk Institute.

“We found that tumours grew much more slowly when AMPK was not present,” said Research Associate Lillian Eichner, the paper’s first author. “That means that AMPK is not always functioning as a tumour suppressor, as we originally thought.”

“Our study shows that the same dysfunction in a genetic circuit that causes non-small-cell lung cancer to begin with is necessary for more mature tumour cells to survive when they don’t have enough nutrients,” elaborated Prof Shaw, director of the Salk Cancer Center and the paper’s senior author. “It’s exciting because not only does it solve a genetic ‘whodunnit’, but it also points to a potential new therapeutic target for a cancer that is often diagnosed very late.”

With more advanced tumours seeming to rely on AMPK to survive, the research suggests that blocking the enzyme could stop the growth of such tumours in some cancers, such as the most common type of lung cancer.

“Previously we were focused on how we could activate AMPK,” said Eichner. “Now that we’ve identified this mechanism, we can shift to how to inhibit it in certain cancers.”

Top image caption: Reuben Shaw and Lillian Eichner. Image credit: Salk Institute.

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