Controlling cancer cells by weakening their defense against reactive oxygen species

Reactive oxygen species (ROS, sometimes loosely referred to as “free radicals”) are generally harmful to cells. Persistent high levels of ROS may damage cells and, eventually, cause cancer. But ROS are also harmful to cancer cells – which, therefore, often develop means of defending themselves against ROS.

Shielding Cancer Cells from Damage

By activating an enzyme involved in the breakdown of glucose, researchers were able to slow the growth of lung cancer cells and increase the harm inflicted by reactive oxygen species (ROS)—byproducts of normal metabolism that can cause damage to the cell in high concentrations. The findings, published Thursday (November 3) in Science Express, could one day be used to make cancer cells more susceptible to cancer treatments and minimize tumor growth.

It’s long been known that cancer cells often have an alternate form of the enzyme pyruvate kinase M1 (PKM1) – PKM2. The new research shows why this is: cancer cells can control the activity of PKM2, which is not possible with PKM1, and this control helps them defend against ROS. Cancer cells need such a defense, because their metabolism differs from normal cell metabolism and is more active, tending to result in higher ROS levels.

The way this works is that both PKM1 and PKM2 play an important role in the glycolysis process, which metabolizes glucose. Glutathione is an antioxidant molecule that can help neutralize ROS. But it also participates in glycolysis, which diverts it from acting as an antioxidant. Cancer cells favor PKM2 over PKM1, because they can lower its level of activity, and therefore leave more glutathione available for antioxidant work.

The researchers equipped cancer cells with a mutant form of PKM2 that, like PKM1, the cells could not control. Such cells were found to sustain more damage from ROS. And when altered cells were implanted in mice, they grew smaller tumors than unmodified cancer cells.

There are fairly obvious ways that these findings may help develop better cancer therapies.

Survival strategy of cancer cells

The team also collaborated with the National Institutes of Health (NIH) Chemical Genomics Center to identify small-molecule PKM2 activators, drugs that keep PKM2 active and thereby prevent cancer cells from using glucose to grow and survive. Treatment of cancer cells with these activators kept PKM2 activity at high levels even under oxidative stress. It also sensitized cells to oxidant-induced death similar to the oxidation-resistant mutant.

“This paper demonstrates that oxidants inhibit PKM2 activity,” says Cantley. “While moderate ROS levels can influence growth signaling and promote proliferation, too much ROS can cause irreversible damage to cells, and lead to their demise. We propose that expression of PKM2 allows cancer cells greater flexibility in manipulating how glucose is metabolized to ensure that ROS concentrations remain low.

“Now that we’ve figured out yet another scheme that cancer uses to survive, we might be able to use small-molecule PKM2 activators to prevent cancer from inhibiting the enzyme,” he adds. “Because radiation therapy and some chemotherapeutic agents are believed to kill cancer cells by inducing excess ROS, there is a possibility that PKM2 activators may improve the efficiency of these therapies.”

Further reading:

Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses

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