Corporate Banner
Satellite Banner
Scientific Communities
Become a Member | Sign in
Home>News>This Article

Metabolic Protein Launches Sugar Feast that Nurtures Brain Tumors

Published: Wednesday, November 28, 2012
Last Updated: Wednesday, November 28, 2012
Bookmark and Share
PKM2 slips into nucleus to promote cancer; potential biomarker and drug approach discovered.

Researchers at The University of Texas MD Anderson Cancer Center have tracked down a cancer-promoting protein's pathway into the cell nucleus and discovered how, once there, it fires up a glucose metabolism pathway on which brain tumors thrive.

They also found a vital spot along the protein's journey that can be attacked with a type of drug not yet deployed against glioblastoma multiforme, the most common and lethal form of brain cancer. Published online by Nature Cell Biology, the paper further illuminates the importance of pyruvate kinase M2 (PKM2) in cancer development and progression.

"PKM2 is very active during infancy, when you want rapid cell growth, and eventually it turns off. Tumor cells turn PKM2 back on - it's overexpressed in many types of cancer," said Zhimin Lu, M.D., Ph.D., the paper's senior author and an associate professor in MD Anderson's Department of Neuro-Oncology.

Lu and colleagues showed earlier this year that PKM2 in the nucleus also activates a variety of genes involved in cell division. The latest paper shows how it triggers aerobic glycolysis, processing glucose into energy, also known as the Warburg effect, upon which many types of solid tumors rely to survive and grow.

"PKM2 must get to the nucleus to activate genes involved in cell proliferation and the Warburg effect," Lu said. "If we can keep it out of the nucleus, we can block both of those cancer-promoting pathways. PKM2 could be an Achilles' heel for cancer."

By pinpointing the complicated steps necessary for PKM2 to penetrate the nucleus, Lu and colleagues found a potentially druggable target that could keep the protein locked in the cell's cytoplasm.

MEK, ERK emerge as targets

The process begins when the epidermal growth factor connects to its receptor on the cell surface. This leads to:

•    Activation of the MEK protein, which in turn activates ERK.
•    ERK sticking a phosphate group to a specific spot on PKM2.
•    Phosphorylation priming PKM2 for a series of steps that culminate in its binding to the protein importin, which lives up to its name by taking PKM2 through the nuclear membrane.

Once in the nucleus, the team showed that PKM2 activates two genes crucial to aerobic glycolysis and another that splices PKM RNA to make even more PKM2.

An experiment applying several kinase-inhibiting drugs to human glioblastoma cell lines showed that only a MEK/ERK inhibitor prevented EGF-induced smuggling of PKM2 into the nucleus. ERK activation then is mandatory for PKM2 to get into the nucleus.

"MEK/ERK inhibitors have not been tried yet in glioblastoma multiforme," Lu said. Phosporylated PKM2 is a potential biomarker to identify patients who are candidates for MEK/ERK inhibitors once those drugs are developed.

MEK inhibitor blocks tumor growth

The researchers also found that the two glycolysis genes activated by PKM2, called GLUT1 and LDHA, are required for glucose consumption and conversion of pyruvate to lactate, crucial factors in the Warburg Effect. Depleting PKM2 in tumor cell lines reduced glucose consumption and lactate production.

In mice, depleting PKM2 blocked the growth of brain tumors. Re-expressing the wild type protein caused tumors to grow. However, re-expression of a PKM2 mutant protein that lost its ability to get into the nucleus failed to promote tumor formation. Experiments in human glioblastoma cell lines showed the same effect.

Injecting the MEK inhibitor selumetinib into tumors inhibited tumor growth, reduced ERK phosphorylation, PKM2 expression and lactate production in mice. In 48 human tumor samples, the team found that activity of EGFR, ERK1/2 and PKM2 were strongly correlated.

Cause of PKM2 overexpression

Lu and colleagues also published a paper in Molecular Cell that revealed a mechanism for overexpression of PKM2 in glioblastoma. They found that EGF receptor activation turns on NF-KB, which leads to a series of events culminating in PKM2 gene activation.

PKM2 levels were measured in tumor samples from 55 glioblastoma patients treated with standard of care surgery, radiation and chemotherapy. The 20 with low PKM2 expression had a median survival of 34.5 months, compared to 13.6 months for the 35 patients with high levels of PKM2.

Level of PKM2 expression in 27 low-grade astrocytomas was about half of the expression found in higher grade glioblastomas.

"In these two papers, we show how PKM2 is overexpressed in tumors, how it gets into the nucleus, that nuclear entry is essential to tumor development, and identified potential drugs and a biomarker that could usefully treat people," Lu said.

Co-authors of the Nature Cell Biology paper are first author Weiwei Yang, Ph.D., Yanhua Zheng, Ph.D., Yan Xia, Ph.D., and Haitao Ji, Ph.D., of MD Anderson's Department of Neuro-Oncology and Brain Tumor Center; Xiaomin Chen, Ph.D., of MD Anderson's Department of Biochemistry and Molecular Biology; Ken Aldape, M.D., MD Anderson's Department of  Pathology; Fang Guo, Ph.D., Nanomedicine Center, Shanghai Research Institute, China Academy of Science; Costas Lyssiotis, Ph.D., and Lewis Cantley, Ph.D., Beth Israel Deaconess Medical Center, Harvard Medical School.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,600+ scientific posters on ePosters
  • More Than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

NASA Award Grant To Develop Platform For Detecting Amino Acids
A University of Texas at Arlington researcher will develop a platform that could help scientists move one step closer to answering whether life may have existed “out there” or if we are really alone in the universe.
Tuesday, September 08, 2015
Electrical Control of Cancer Cells
Research led by scientists at The University of Texas Health Science Center at Houston (UTHealth) has revealed a new electrical mechanism that can control these switches.
Wednesday, August 26, 2015
Mass Extinctions Can Accelerate Evolution
A computer science team at The University of Texas at Austin has found that robots evolve more quickly and efficiently after a virtual mass extinction modeled after real-life disasters such as the one that killed off the dinosaurs.
Tuesday, August 18, 2015
Critical New Insights on DNA Repair
The enzyme fumarase is key to reversing genetic damage leading to cancer and therapy resistance.
Wednesday, August 05, 2015
Researchers Develop Vaccine that Protects Primates Against Ebola
A collaborative team from The University of Texas Medical Branch at Galveston and the National Institutes of Health have developed an inhalable vaccine that protects primates against Ebola.
Thursday, July 23, 2015
Can Cell Cycle Protein Prevent or Kill Breast Cancer Tumors?
An MD Anderson study has shown the potential of a simple molecule involved in cancer metabolism as a powerful therapeutic.
Monday, July 20, 2015
Partly Human Yeast Show A Common Ancestor’s Lasting Legacy
Edward Marcotte and his colleagues at the University of Texas at Austin created hundreds of strains of humanized yeast by inserting into each a single human gene and turning off the corresponding yeast gene.
Tuesday, May 26, 2015
Cancer-Causing Virus Blocks Human Immune Response
Epstein-Barr virus shown to outwit the human immune response using microRNAs.
Wednesday, January 28, 2015
Researchers Reveal Genomic Diversity Of Individual Lung Tumors
Findings suggest sequencing a single region of a localized tumor will identify driver mutations.
Friday, October 10, 2014
How Fluid Flow Influences Neuron Growth
A University of Texas at Arlington team exploring how neuron growth can be controlled in the lab and, possibly, in the human body has published a new paper in Nature Scientific Reports on how fluid flow could play a significant role.
Wednesday, October 08, 2014
3-in-1 Spectroscopy System Improves Skin Cancer Detection
The new device may detect cancerous skin lesions early on, leading to better treatment outcomes and ultimately saving lives.
Thursday, August 07, 2014
Method Developed at UT Arlington Allows Quantitative Nanoscopic Imaging Through Silicon
A team of scientists has figured out how to quantitatively observe cellular processes taking place on so-called “lab on a chip” devices in a silicon environment.
Monday, October 07, 2013
Chlamydia Protein has an Odd Structure
Research could lead to new ways to combat this sexually transmitted disease.
Thursday, June 13, 2013
Researchers Reveal New Enzyme that Acts as Innate Immunity Sensor
Two studies by researchers at UT Southwestern Medical Center could lead to new treatments for lupus and other autoimmune diseases and strengthen current therapies for viral, bacterial, and parasitic infections.
Monday, February 18, 2013
Unique Peptide Could Treat Cancers, Neurological Disorders, Infectious Diseases
Scientists have synthesized a peptide that shows potential for pharmaceutical development through an ability to induce a cell-recycling process called autophagy.
Monday, February 18, 2013
Scientific News
Genetic Defences of Bacteria Don’t Aid Antibiotic Resistance
Genetic responses to the stresses caused by antibiotics don’t help bacteria to evolve a resistance to the medications, according to a new study by Oxford University researchers.
Detecting HIV Diagnostic Antibodies with DNA Nanomachines
New research may revolutionize the slow, cumbersome and expensive process of detecting the antibodies that can help with the diagnosis of infectious and auto-immune diseases such as rheumatoid arthritis and HIV.
Snapshot Turns T Cell Immunology on its Head
New research may have implications for 1 diabetes sufferers.
Tolerant Immune System Increases Cancer Risk
Researchers have found that individuals with high immunoCRIT ratios may have an increased risk of developing certain cancers.
Developing a Gel that Mimics Human Breast for Cancer Research
Scientists at the Universities of Manchester and Nottingham have been funded to develop a gel that will match many of the biological structures of human breast tissue, to advance cancer research and reduce animal testing.
Cell's Waste Disposal System Regulates Body Clock Proteins
New way to identify interacting proteins could identify potential drug targets.
New Approach to Treating Heparin-induced Blood Disorder
A potential treatment for a serious clotting condition that can strike patients who receive heparin to treat or prevent blood clots may lie within reach by elucidating the structure of the protein complex at its root.
Horse Illness Shares Signs of Human Disease
Horses with a rare nerve condition have similar signs of disease as people with conditions such as Alzheimer’s, a study has found.
How a Molecular Motor Untangles Protein
Diseases such as Alzheimer’s, Parkinson’s and prion diseases, all involve “tangled” proteins.
Compound Doubles Up On Cancer Detection
Researchers have found that tagging a pair of markers found almost exclusively on a common brain cancer yields a cancer signal that is both more obvious and more specific to cancer.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos