Featured Research

from universities, journals, and other organizations

Leucine deprivation proves deadly to malignant melanoma cells

Date:
June 6, 2011
Source:
Whitehead Institute for Biomedical Research
Summary:
Researchers have found that depriving human melanoma cells of the 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.

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.

Related Articles


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 amino acids 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 melanoma cells 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 melanoma 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."

This research was supported by the National Institutes of Health (NIH), the U.S. Department of Defense (DoD), the Jane Coffin Childs Memorial Fund for Medical Research, and the American Brain Tumor Association.

David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.



Story Source:

The above story is based on materials provided by Whitehead Institute for Biomedical Research. Note: Materials may be edited for content and length.


Journal Reference:

  1. Joon-Ho Sheen, Roberto Zoncu, Dohoon Kim, David M. Sabatini. Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell, Volume 19, Issue 5, 613-628, 17 May 2011 DOI: 10.1016/j.ccr.2011.03.012

Cite This Page:

Whitehead Institute for Biomedical Research. "Leucine deprivation proves deadly to malignant melanoma cells." ScienceDaily. ScienceDaily, 6 June 2011. <www.sciencedaily.com/releases/2011/05/110516121417.htm>.
Whitehead Institute for Biomedical Research. (2011, June 6). Leucine deprivation proves deadly to malignant melanoma cells. ScienceDaily. Retrieved October 25, 2014 from www.sciencedaily.com/releases/2011/05/110516121417.htm
Whitehead Institute for Biomedical Research. "Leucine deprivation proves deadly to malignant melanoma cells." ScienceDaily. www.sciencedaily.com/releases/2011/05/110516121417.htm (accessed October 25, 2014).

Share This



More Health & Medicine News

Saturday, October 25, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

IKEA Desk Converts From Standing to Sitting With One Button

IKEA Desk Converts From Standing to Sitting With One Button

Buzz60 (Oct. 24, 2014) — IKEA is out with a new convertible desk that can convert from a sitting desk to a standing one with just the push of a button. Jen Markham explains. Video provided by Buzz60
Powered by NewsLook.com
Ebola Protective Suits Being Made in China

Ebola Protective Suits Being Made in China

AFP (Oct. 24, 2014) — A factory in China is busy making Ebola protective suits for healthcare workers and others fighting the spread of the virus. Duration: 00:38 Video provided by AFP
Powered by NewsLook.com
WHO: Millions of Ebola Vaccine Doses by 2015

WHO: Millions of Ebola Vaccine Doses by 2015

AP (Oct. 24, 2014) — The World Health Organization said on Friday that millions of doses of two experimental Ebola vaccines could be ready for use in 2015 and five more experimental vaccines would start being tested in March. (Oct. 24) Video provided by AP
Powered by NewsLook.com
Doctor in NYC Quarantined With Ebola

Doctor in NYC Quarantined With Ebola

AP (Oct. 24, 2014) — An emergency room doctor who recently returned to the city after treating Ebola patients in West Africa has tested positive for the virus. He's quarantined in a hospital. (Oct. 24) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins