Cells enter a state of dormancy as tissues starved of oxygen become increasingly acidic, according to a new study. Published in the journal Cell, the study found that this dormancy, thought to be a major cause of drug resistance and disease relapses in cancer, might be relatively easy to reverse when it is induced by acidity. The finding could help improve a variety of cancer therapies.
Walton et al describe how acidity makes oxygen-starved cancer cells dormant and drug resistant. Image credit: Walton et al, doi: 10.1016/j.cell.2018.05.009.
The study detailed how, in response to acidity, cells turn off a critical molecular switch known as mTORC1 that, in ordinary conditions, gauges the availability of nutrients before giving cells the green light to grow and divide.
That event shuts down the cell’s production of proteins, disrupting their metabolic activity and circadian clocks, and pushing them into a quiescent state.
This acid-mediated effect might be relatively easy to reverse — a finding that could help improve a variety of cancer therapies.
“In tumors grafted into mice, we see mTOR activity in spotty places where there’s oxygen,” said co-lead author Professor Chi Van Dang, scientific director of the Ludwig Institute for Cancer Research and a researcher at the Wistar Institute.
“But if you add baking soda to the drinking water given to those mice, the entire tumor lights up with mTOR activity. The prediction would be that by reawakening these cells, you could make the tumor far more sensitive to therapy.”
Baking soda had previously been reported to enhance cancer immunotherapy by Dr. Robert Gillies of the H. Lee Moffitt Cancer Center, one of the study authors, though the mechanism underlying the effect was unclear.
Professor Dang and colleagues discovered that mechanism through an intricate series of experiments.
It centers on the behavior of lysosomes — a sack-like cellular organelle that digests proteins and that mTOR moves to when it is ready for action.
The researchers show that in acidic conditions protein motors propel lysosomes carrying mTOR away from the area around the nucleus, where they’re ordinarily located.
This separates mTOR from a protein required for its activation, RHEB, which continues to hang around at that location.
Lacking one of its key activation signals, mTOR remains dormant, suspending the synthesis of proteins — including the components of the cell’s molecular clock — along with most metabolic activity.
“Cells don’t want to make proteins or other biomolecules when they’re under stress. They want to slow things down and only awaken when things return to normal,” Professor Dang said.
The scientists show that baking soda can reverse this effect.
When given to mice in their drinking water, it surprisingly sufficed to neutralize the acidity of hypoxic patches in tumors. This sent lysosomes zipping back to the nuclear periphery in cells — where RHEB was waiting — and restored the activity of mTOR.
All this is relevant to cancer because researchers have long known that quiescent cells cannot typically be killed by chemotherapy.
Notably, the study authors also found that T cell activation, which is essential to most immunotherapies, is similarly compromised under acidic conditions.
“We started out with a question about oxygen starvation and the circadian clock, and we ended up discovering a new mechanism by which acidic conditions in tissues shut off a lot of things — including the cell’s molecular clock,” Professor Dan said.
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Zandra E. Walton et al. Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR. Cell, published online May 31, 2018; doi: 10.1016/j.cell.2018.05.009