Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

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

Join For Free

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 3,300+ scientific posters on ePosters
  • More than 4,800+ 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 TechnologyNetworks.com 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

Fix for 3-Billion-Year-Old Genetic Error
Researchers at The University of Texas at Austin have developed a fix that allows RNA to accurately proofread for the first time.
Monday, June 27, 2016
New Breast Cancer Staging System
Neo-Bioscore adds HER2 status into previously developed system.
Monday, March 21, 2016
Mechanism of Tumor Suppressing Gene Uncovered
The most commonly mutated gene in cancer,p53, works to prevent tumor formation by keeping mobile elements in check that otherwise lead to genomic instability, UT Southwestern Medical Center researchers have found.
Tuesday, January 26, 2016
Gene-Editing Halts DMD Progression
Using a new gene-editing technique, a team of scientists from UT Southwestern Medical Center stopped progression of Duchenne muscular dystrophy (DMD) in young mice.
Tuesday, January 05, 2016
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
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
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
Ancient Enzymes Function like Nanopistons to Unwind RNA
Molecular biologists have solved one of the mysteries of how double-stranded RNA is remodeled inside cells in both their normal and disease states.
Wednesday, September 05, 2012
New Genomic Technique Uncovers Coral Transcriptome
Researchers have uncovered the larval transcriptome of a reef-building coral by utilizing a new technique for cDNA preparation.
Tuesday, May 12, 2009
Genetic Variation Raises HIV Risk in People of African Descent
A genetic variation that may have protected people of African descent against a pandemic of malaria long ago now appears to increase their susceptibility to HIV infection.
Wednesday, July 23, 2008
When she's Turned on, Some of Her Genes Turn Off
When a female is attracted to a male, entire suites of genes in her brain turn on and off, show biologists from The University of Texas at Austin studying swordtail fish.
Thursday, December 20, 2007
Welch Foundation Gives $1.6 Million for Drug Discovery Research
UTMB scientist will lead computational chemistry program at John S. Dunn Gulf Coast Consortium for Chemical Genomics.
Monday, September 17, 2007
Scientific News
Liquid Biopsies: Miracle Diagnostic or Next New Fad?
Thanks to the development of highly specific gene-amplification and sequencing technologies liquid biopsies access more biomarkers relevant to more cancers than ever before.
Colon Cancer Blocked in Mice
Case Western Reserve University Researchers block common type of colon cancer tumour in mice, laying groundwork for human clinical trial.
Discovered Through ‘Big Data’ Analysis
Researchers at the SBP have identified over 100 new genetic regions that affect the immune response to cancer.
New Therapeutic Targets For Small Cell Lung Cancer Identified
Researchers at UTSW Medical Center have identified a protein termed ASCL1 that is essential to the development of small cell lung cancer and that, when deleted in the lungs of mice, prevents the cancer from forming.
Deciphering Inactive X Chromosomes
Untangling the Barr body of inactive X chromosomes valuable for understanding chromosome structure and gene expression.
Micro Disease-Detecting Senor Created
Researchers at McMaster University have created a microscopic disease-detecting sensor that can turn on to detect trace amounts of substances.
Liquid Biopsies Treating Ovarian Cancer
Researchers have discovered a promising monitor and treat recurrence of ovarian cancer. Detecting cancer long before tumours reappear.
Uncovering a New Principle in Chemotherapy Resistance in Breast Cancer
The NIH study has revealed an entirely unexpected process for acquiring drug resistance that bypasses the need to re-establish DNA damage repair in breast cancers that have mutant BRCA1 or BRCA2 genes.
Understanding Treatment Resistant Melanoma
Researchers have determined how advanced melanoma becomes resistant; a development toward developing treatments.
Investigating ‘Black Box’ of Human Genetics
Investigations into inactive X chromosomes have shown unusual DNA repeat elements are essential for maintaining 3D structure.
Skyscraper Banner

SELECTBIO Market Reports
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
3,300+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,800+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!