Leucine deprivation proves deadly to malignant melanoma cells

May 16, 2011

Whitehead Institute researchers have found that depriving human melanoma cells of the essential amino acid leucine can be lethal to the cells, suggesting a possible strategy for therapeutic intervention.

The researchers observed the effect in melanoma cells with a mutation in the RAS/MEK signaling pathway—the most common mutation found in the deadliest form of skin cancer.

Leucine is one of nine essential humans must ingest, as we are unable to synthesize them. These nine, along with 12 non-essential amino acids, are the building blocks of proteins used in muscle production and normal cell functions. Cellular amino acid levels and other nutrients are monitored by the mTOR pathway. Typically, when levels of one or more amino acids drop too low, the mTOR pathway is turned off, which activates a process called autophagy.

During autophagy, the cell attempts to boost amino acid levels by breaking down the cell's protein-based structures back into their amino acid components. This is similar to the entire body breaking down fat and muscle when it is on a diet. For a cell, autophagy is a short-term survival mechanism.

According to their paper published in the May 17 issue of Cancer Cell, researchers in the lab of Whitehead Institute Member David Sabatini found that melanoma cells with RAS/MEK pathway mutations short-circuit this chain of events.

"The odd thing is that if you remove this one essential amino acid, leucine, the melanoma cells don't activate autophagy," says Sabatini, who is also a professor of biology at MIT and a Howard Hughes Medical Institute (HHMI) investigator. "Because leucine is essential, they eventually die. Potentially, that could be used as a way of targeting the melanoma cells if one could mimic the lack of leucine."

When melanoma cells with RAS/MEK pathway mutations are deprived of leucine, mTOR does not sense it, so mTOR does not turn off, and autophagy never begins. Instead, the cells behave as if there were no nutrient shortage until they reach a metabolic crisis and die.

Although cells in a test tube can be deprived of leucine completely, removing leucine from a mouse or a human is almost impossible, due to large leucine reservoirs in muscles. To test how leucine deprivation works in an animal model, Joon-Ho Sheen, who is first author of the Cancer Cell paper, implanted human melanoma tumors with RAS/MEK pathway mutations into mice. He then fed the mice a leucine-free diet. Within a few days, the leucine concentration in the mice's blood dropped from about 110 micromoles to 60 or 70 micromoles. As the blood leucine levels dropped, so too did the leucine levels within the mice's cells. Still, the drop in leucine wasn't sufficient to kill the melanoma cells in vivo.

Sheen then gave the mice the drug chloroquine along with a leucine-free diet. Chloroquine, which is an anti-malaria drug, inhibits autophagy. With the one-two punch of chloroquine and a leucine-free diet, the died, significantly reducing tumor sizes compared with mice fed either a normal diet or a leucine-free diet without chloroquine.

For Sheen, these results raised more questions, particularly with regard to potential therapeutic applications.

"Thanks to the pioneering work by others in the autophagy field, we were able to show that leucine deprivation triggers apoptosis in cells. I think our work provides a framework, but there are many areas to fill in," says Sheen, who is a postdoctoral researcher in the Sabatini lab. "In practice, how can you deprive just leucine in humans? Maybe using some sort of enzyme that degrades leucine or a small molecule inhibitor that blocks leucine's uptake by cells. And we need a better way to target autophagy; chloroquine isn't very efficient at this. And those are just the immediate, foreseeable issues."

Explore further: Why the Switch Stays On: Scientists Discover Reasons Behind Cancerous Cellular Interactions

More information: "Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo" Cancer Cell, May 16, 2011.

Related Stories

Cell recycling protects tumor cells from anti-cancer therapy

March 6, 2008

Cells have their own recycling system: Discarded cellular components, from individual proteins through to whole cellular organs, are degraded and the building blocks re-used in a different place. The scientific term for this ...

Amino acid supplement makes mice live longer

October 5, 2010

When mice are given drinking water laced with a special concoction of amino acids, they live longer than your average mouse, according to a new report in the October issue of Cell Metabolism. The key ingredients in the supplemental ...

Production of mustard oils: On the origin of an enzyme

March 17, 2011

(PhysOrg.com) -- In the evolutionary arms race, small changes can be sufficient to gain a crucial advantage over the enemy. Scientists at the Max Planck Institute for Chemical Ecology found out recently that the ancestor ...

Recommended for you

Oxygen can impair cancer immunotherapy in mice

August 25, 2016

Researchers have identified a mechanism in mice by which anticancer immune responses are inhibited within the lungs, a common site of metastasis for many cancers. This mechanism involves oxygen inhibition of the anticancer ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.