Could we use cell metabolism in the fight against hard-to-treat tumors?
Some tumors are hard to treat because while at first they respond to cancer drugs, some cells are able to survive and seed new tumors.
The surviving cells do this by increasing a “self-eating” process through which they eliminate waste, remove faulty components and pathogens, and recycle essential molecular building blocks.
The process, known as autophagy, delivers the waste to cell compartments called lysosomes. These contain different types of enzymes for digesting and breaking down the various materials.
Autophagy is also a survival mechanism that switches on when nutrients are scarce and switches off again when nutrients are plentiful.
“We found that cell metabolism significantly influences the ability to begin autophagy,” says lead investigator Carol Mercer, an associate professor in the Division of Hematology and Oncology at the University of Cincinnati in Ohio.
She and her colleagues report their findings — which reveal “the dynamic and metabolic regulation of autophagy” — in a paper that is now published in the journal Cell Reports.
Control of autophagy
Two types of enzyme control autophagy in cells: one is AMP-activated protein kinase (AMPK), and the other is mammalian target of rapamycin (mTOR).
Treatments for some cancers already use drugs that trigger AMPK or target mTOR, and they are also being investigated for use in other cancer treatments.
For these reasons, Mercer explains, it is “important to understand how they affect this tumor cell survival pathway.”
Every cell contains tiny powerhouses called mitochondria that make energy for the cells. Energy production in mitochondria occurs in several stages, each involving a protein complex. The first stage uses one called mitochondrial complex I.
People who are deficient in complex I can develop several health problems, including some that affect the heart, liver, brain, and nerves.
Mercer and her colleagues demonstrated that mitochondrial complex I also plays a key role in triggering and increasing autophagy and regulating its duration.
Preventing and promoting autophagy
The scientists found that genetic faults in mitochondrial complex I prevented autophagy triggered by mTOR inhibitors. They also showed how two antidiabetic drugs — phenformin and metformin — had the same effect.
Conversely, it was possible to increase autophagy using methods “that increased mitochondrial metabolism,” note the authors.
Overall, the study reveals new insights into the dynamic role of cell metabolism in autophagy and suggests, according to Mercer, “new therapeutic strategies for cancer, neurodegenerative, and mitochondrial diseases.”
Most of the work to discover how metabolism affects autophagy and how to use it to increase or decrease the process was done using cultured cells.
It builds on earlier work by one member of the team, who had discovered that while inhibiting mTOR could treat liver cancer, it also increased autophagy.
“Our data demonstrate the importance of metabolism in the regulation of autophagy, increase our understanding of clinically relevant drugs that are important for cancer, and suggest new strategies to increase or inhibit autophagy.”