Forum für Wissenschaft, Industrie und Wirtschaft

Hauptsponsoren:     3M 
Datenbankrecherche:

 

Metabolic protein launches sugar feast that nurtures brain tumors

27.11.2012
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-?B, 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.

This research was funded by grants from the National Institutes of Health (numbers 2RO1CA109035, RO1GM068566 and RO1GM56302), MD Anderson's Cancer Center Support Grant (CA16672) from the National Cancer Institute; and a research grant from the Cancer Prevention and Research Institute of Texas.

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 41 comprehensive cancer centers designated by the National Cancer Institute. For nine of the past 11 years, including 2012, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.

Scott Merville | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Health and Medicine:

nachricht Discovery of a novel gene for hereditary colon cancer
29.07.2016 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht New evidence: How amino acid cysteine combats Huntington's disease
27.07.2016 | Johns Hopkins Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Neue Bildgebungsmethode macht Sauerstoffgehalt in Gewebe sichtbar

Wie blickt man in den menschlichen Körper, ohne zu operieren? Die Suche nach neuen Lösungen ist nach wie vor eine wichtige Aufgabe der Medizinforschung. Eine der großen Herausforderungen auf diesem Feld ist es, Sauerstoff in Gewebe sichtbar zu machen. Ein Team um Prof. Vasilis Ntziachristos, Inhaber des Lehrstuhls für Biologische Bildgebung an der Technischen Universität München (TUM) und Direktor des Instituts für Biologische und Medizinische Bildgebung am Helmholtz Zentrum München, hat dazu einen neuen Ansatz entwickelt.

Einen Königsweg, um den Sauerstoffgehalt in Gewebe sichtbar zu machen, schien es bislang nicht zu geben. Viele unterschiedliche Verfahren wurden ausprobiert,...

Im Focus: Wie biologische Vielfalt das Ohr fit macht

Göttinger Hörforschung mit neuen Erkenntnissen: Das Ohr setzt Synapsen mit verschiedenen Eigenschaften ein, um unterschiedlich lauten Schall zu verarbeiten. Forschungsergebnisse veröffentlicht in der Fachzeitschrift „Proceedings of the National Academy of Sciences“

Der menschliche Hörsinn verarbeitet einen immensen Bereich an Lautstärken. Wie schafft es das Ohr, etwa über eine Million Schalldruck-Variationen zu...

Im Focus: Ultrakompakter Photodetektor

Der Datenverkehr wächst weltweit. Glasfaserkabel transportieren die Informationen mit Lichtgeschwindigkeit über weite Entfernungen. An ihrem Ziel müssen die optischen Signale jedoch in elektrische Signale gewandelt werden, um im Computer verarbeitet zu werden. Forscher am KIT haben einen neuartigen Photodetektor entwickelt, dessen geringer Platzbedarf neue Maßstäbe setzt: Das Bauteil weist eine Grundfläche von weniger als einem Millionstel Quadratmillimeter auf, ohne die Datenübertragungsrate zu beeinträchtigen, wie sie im Fachmagazin Optica nun berichten. (DOI: 10.1364/OPTICA.3.000741)

Die neuentwickelten Photodetektoren, die weltweit kleinsten Photodetektoren für die optische Datenübertragung, eröffnen die Möglichkeit, durch integrierte...

Im Focus: Self-assembling nano inks form conductive and transparent grids during imprint

Transparent electronics devices are present in today’s thin film displays, solar cells, and touchscreens. The future will bring flexible versions of such devices. Their production requires printable materials that are transparent and remain highly conductive even when deformed. Researchers at INM – Leibniz Institute for New Materials have combined a new self-assembling nano ink with an imprint process to create flexible conductive grids with a resolution below one micrometer.

To print the grids, an ink of gold nanowires is applied to a substrate. A structured stamp is pressed on the substrate and forces the ink into a pattern. “The...

Im Focus: Neues Forschungsnetzwerk für Mikrobiomforschung

Mikroben und Viren haben weitreichenden Einfluss auf die Gesundheit von Mensch und Tier. Die neu gegründete "Austrian Microbiome Initiative" (AMICI) fördert die nationale Mikrobiomforschung und vernetzt MedizinerInnen und ForscherInnen verschiedenster Fachrichtungen zur Nutzung von Synergien.

Bakterien, Archaeen, Pilze, Viren – Milliarden von Mikroorganismen leben in Symbiose in und auf Menschen und Tieren. Diese mikroskopisch kleinen Lebewesen...

Alle Focus-News des Innovations-reports >>>

Anzeige

Anzeige

IHR
JOB & KARRIERE
SERVICE
im innovations-report
in Kooperation mit academics
Veranstaltungen

BAuA lädt zur Konferenz „Arbeiten im Büro der Zukunft“ ein

29.07.2016 | Veranstaltungen

Fachkongress zu additiven Fertigungsverfahren am 14. und 15. September in Aachen

28.07.2016 | Veranstaltungen

Rheumatologen tagen in Frankfurt: Mehr Forschung für Rheuma gefordert

28.07.2016 | Veranstaltungen

 
B2B-VideoLinks
Weitere VideoLinks >>>
Aktuelle Beiträge

Forschung gibt Impulse für Innovationen

29.07.2016 | Förderungen Preise

Molekulare Störenfriede statt Antibiotika? Wie Proteine Kommunikation zwischen Bakterien verhindern

29.07.2016 | Biowissenschaften Chemie

Internationales Forscherteam deckt grundlegende Eigenschaften des Spin-Seebeck-Effekts auf

29.07.2016 | Physik Astronomie