Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Learning 1 of cancer's tricks

24.08.2012
Caltech chemists determine 1 way tumors meet their growing needs

Behaving something like ravenous monsters, tumors need plentiful supplies of cellular building blocks such as amino acids and nucleotides in order to keep growing at a rapid pace and survive under harsh conditions.


A computational model depicts a PFK1 enzyme with the sugar GlcNAc attached (left). Comparing this model to that showing PFK1 complexed to a molecule that activates the enzyme (right) suggests how addition of GlcNAc may inhibit enzymatic activity.

Credit: Caltech/Yi et al.

How such tumors meet these burgeoning demands has not been fully understood. Now chemists at the California Institute of Technology (Caltech) have shown for the first time that a specific sugar, known as GlcNAc ("glick-nack"), plays a key role in keeping the cancerous monsters "fed." The finding suggests new potential targets for therapeutic intervention.

The new results appear in this week's issue of the journal Science.

The research team—led by Linda Hsieh-Wilson, professor of chemistry at Caltech—found that tumor cells alter glycosylation, the addition of carbohydrates (in this case GlcNAc) to their proteins, in response to their surroundings. This ultimately helps the cancerous cells survive. When the scientists blocked the addition of GlcNAc to a particular protein in mice, tumor-cell growth was impaired.

The researchers used chemical tools and molecular modeling techniques developed in their laboratory to determine that GlcNAc inhibits a step in glycolysis (not to be confused with glycosylation), a metabolic pathway that involves 10 enzyme-driven steps. In normal cells, glycolysis is a central process that produces high-energy compounds that the cell needs to do work. But Hsieh-Wilson's team found that when GlcNAc attaches to the enzyme phosphofructokinase 1 (PFK1), it suppresses glycolysis at an early phase and reroutes the products of previous steps into a different pathway—one that yields the nucleotides a tumor needs to grow, as well as molecules that protect tumor cells. So GlcNAc causes tumor cells to make a trade—they produce fewer high-energy compounds in order to get the products they need to grow and survive.

"We have identified a novel molecular mechanism that cancer cells have co-opted in order to produce intermediates that allow them to grow more rapidly and to help them combat oxidative stress," says Hsieh-Wilson, who is also an investigator with the Howard Hughes Medical Institute.

This is not the first time scientists have identified a mechanism by which tumor cells might produce the intermediates they need to survive. But most other mechanisms have involved genetic alterations, or mutations—permanent changes that lead to less active forms of enzymes, for example. "What's unique here is that the addition of GlcNAc is dynamic and reversible," says Hsieh-Wilson. "This allows a cancer cell to more rapidly alter its metabolism depending on the environment that it encounters."

In their studies, Hsieh-Wilson's team found that this glycosylation—the addition of GlcNAc to PFK1—is enhanced under conditions associated with tumors, such as low oxygen levels. They also found that glycosylation of PFK1 was sensitive to the availability of nutrients. If certain nutrients were absent, glycosylation was increased, and the tumor was able to compensate for the dearth of nutrients by changing the cell's metabolism.

When the researchers analyzed human breast and lung tumor tissues, they found GlcNAc-related glycosylation was elevated two- to fourfold in the majority of tumors relative to normal tissue from the same patients. Then, working with mice injected with human lung-cancer cells, the researchers replaced the existing PFK1 enzymes with either the normal PFK1 enzyme or a mutant form that could no longer be glycosylated. The mice with the mutant form of PFK1 showed decreased tumor growth, demonstrating that blocking glycosylation impairs cancerous growth.

The work suggests at least two possible avenues for future investigations into fighting cancer. One would be to develop compounds that prevent PFK1 from becoming glycosylated, similar to the mutant PFK1 enzymes in the present study. The other would be to activate PFK1 enzymes in order to keep glycolysis operating normally and help prevent cancer cells from altering their cellular metabolism in favor of cancerous growth.

Hsieh-Wilson's group has previously studied GlcNAc-related glycosylation in the brain. They have demonstrated, for example, that the addition of GlcNAc to a protein called CREB inhibits the protein's ability to turn on genes needed for long-term memory storage. On the other hand, they have also shown that having significantly lower levels of GlcNAc in the forebrain leads to neurodegeneration. "The current thinking is that there's a balance between too little and too much glycosylation," says Hsieh-Wilson. "Being at either extreme make things go awry, whether it's in the brain or in the case of cancer cells."

Additional Caltech coauthors on the paper, "Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism," were lead author Wen Yi, a postdoctoral scholar in Hsieh-Wilson's group; Peter Clark, a former graduate student in Hsieh-Wilson's group; and William Goddard III, the Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics. Daniel Mason and Eric Peters of the Genomics Institute of the Novartis Research Foundation and Marie Keenan, Collin Hill, and Edward Driggers of Agios Pharmaceuticals were also coauthors.

The work was supported by the National Institutes of Health, the Department of Defense Breast Cancer Research Program, and a Tobacco-Related Disease Research Program postdoctoral fellowship.

Written by Kimm Fesenmaier

Brian Bell | EurekAlert!
Further information:
http://www.caltech.edu

More articles from Life Sciences:

nachricht Repairing damaged hearts with self-healing heart cells
22.08.2017 | National University Health System

nachricht Biochemical 'fingerprints' reveal diabetes progression
22.08.2017 | Umea University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Cholesterol-lowering drugs may fight infectious disease

22.08.2017 | Health and Medicine

Meter-sized single-crystal graphene growth becomes possible

22.08.2017 | Materials Sciences

Repairing damaged hearts with self-healing heart cells

22.08.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>