Navigation Links
Cancer-promoting protein is vital to safe division of tumor cells

HOUSTON Researchers have caught a protein they previously implicated in a variety of cancer-promoting roles performing a vital function in cell division, survival and development of brain tumors.

In a paper published in Molecular Cell, Zhimin Lu, Ph.D., professor of Neuro-Oncology at The University of Texas MD Anderson Cancer Center and colleagues report how a tumor-specific protein flips a crucial switch in an irregular mechanism for mitosis that allows cancer cells to safely divide.

"Our research shows that tumor cells rely heavily on a distinct mechanism for orderly cell division that's driven by oncogene-induced pyruvate kinase M2," Lu said.

After a cell begins division by replicating all of its chromosomes, mitosis separates them into two identical sets of chromosomes for both cells. After mitosis, cytokinesis completes cell divison.

"Without PKM2 regulating a checkpoint in mitosis, the tumor cell would not successfully divide," Lu said. "Depleting PKM2 led to an uneven distribution of DNA to the two new cells, triggering programmed cell death, or apoptosis, of those cells after division."

"This new, additional role for PKM2 in cancer development and survival may provide a molecular basis for diagnosing and treating tumors with upregulated PKM2," Lu said. He and his colleagues have now identified four specific mechanisms by which PKM2 promotes cancer development.

PKM2 regulation of mitosis worsens tumors in mice; affects human glioblastoma

The key relationship between PKM2 activity and mitosis uncovered by the researchers led to rapid brain tumor growth when activated in mice, while blocking it reduced tumor volume by 83 percent and more than doubled survival from about 20 days to beyond 40 days.

Analysis of 50 human glioblastoma multiforme tumors and 50 lung cancer tumors confirmed the relationship in human cancer and indicated an effect on survival for patients with glioblastoma, the most common and lethal form of brain tumor.

PKM2 can act as a protein kinase, which gives orders to other proteins by attaching phosphate groups to them. While it plays a normal role in sugar metabolism, PKM2 also actively promotes cell growth during infancy when such growth is desired.

Usually, Lu said, it eventually turns off, but tumor cells reactivate PKM2, and it is famously overexpressed in solid tumors. This tumor-specific PKM2 is activated by the epidermal growth factor receptor (EGFR), which is overactive in a variety of cancers.

Deplete PKM2 in mitosis, tumor cells abnormally divide in multiple cancer types

A series of experiments in glioblastoma cell lines revealed that PKM2 phosphorylates a protein called Bub3, activating it to interact with others in a protein complex that assures orderly and equal chromosome separation.

Depleting PKM2 blocked Bub3 activation, leading to an increase in cells with abnormal numbers of chromosomes and programmed cell death.

The team confirmed its findings in human breast, prostate, lung, pancreatic and colon cancer cell lines.

PKM2-induced Bub3 activation was essential for development of brain tumors in mice.

Experiments in the 50 glioblastoma and lung cancer tumors confirmed that phosphorylation of Bub3 correlates with phosphorylation of H3-S10, a marker of cell mitosis in tumor cells.

With low Bub3 phosphorylation, glioblastoma patients live longer

Among the 50 glioblastoma patients, the 15 with low levels of Bub3 phosphorylation had a median survival of 69.8 weeks, compared to 40.5 weeks for the 35 patients with high levels of Bub3 activation.

Previous research by Lu and colleagues showed PKM2, usually active outside the cell nucleus, slips into the nucleus where it promotes cancer formation, growth and survival by:

  • Activating an important transcription co-factor that, in turn, activates other cancer-promoting genes.

  • Phosphorylating the histone protein H3, loosening the packaging of DNA and leading to the activation of cell division genes.

  • Inducing expression of glycolytic genes (including PKM2 itself) and triggering a glucose metabolism mechanism called the Warburg effect that nourishes tumor cells.

Potential avenues for thwarting these effects identified in their experiments include two classes of drug that inhibit SRC and MEK activity.

"Our research further highlights the importance of PKM2 in human cancers and of developing ways to target its activity and use it as a biomarker to guide treatment," Lu said.


Contact: Scott Merville
University of Texas M. D. Anderson Cancer Center

Related medicine news :

1. Scientists catch EGFR passing a crucial message to cancer-promoting protein
2. Same protein that fires up cancer-promoting Erk also blocks its activation
3. Novel mechanism through which normal stromal cells become cancer-promoting cells identified
4. Metabolic protein wields phosphate group to activate cancer-promoting genes
5. Skp2 activates cancer-promoting, glucose-processing Akt
6. Penn study delivers protein across blood-brain barrier to degrade Alzheimers plaques
7. Study identifies protein that helps developing germ cells wipe genes clean of past imprints
8. Protein in prostate biopsies signals increased cancer risk
9. Cardiovascular Institute: Unfolded protein response contributes to sudden death in heart failure
10. New family of proteins linked to major role in cancer
11. CNIO scientists create the first large catalog of interactions between drugs and proteins
Post Your Comments:
(Date:6/27/2016)... ... June 27, 2016 , ... "FCPX editors can now reveal ... Final Cut Pro X," said Christina Austin - CEO of Pixel Film Studios. ... Cut Pro X users can now reveal the media of their split screens ...
(Date:6/27/2016)... (PRWEB) , ... June 27, ... ... in the patient payment industry today announced its strategic partnership with Connance, ... system workflows. , The two companies’ proven, proprietary technology combine to provide ...
(Date:6/27/2016)... KS (PRWEB) , ... June 27, 2016 , ... ... retailers of Eyeglasses . , Millions of individuals in the United States and ... have become a way to both correct vision and make a fashion statement. Even ...
(Date:6/26/2016)... ... June 26, 2016 , ... On June 10-11, 2016, ... the 2016 Cereal Festival and World’s Longest Breakfast Table in Battle Creek, MI, where ... city’s history as home to some of the world’s leading providers of cereal and ...
(Date:6/26/2016)... ... 26, 2016 , ... PawPaws brand pet supplements owned by Whole ... enhance the health of felines. The formula is all-natural and is made from Chinese ... PawPaws Cat Kidney Support Supplement Soft Chews are Astragalus Root Extract and ...
Breaking Medicine News(10 mins):
(Date:6/26/2016)... , June 26, 2016 ... value-based care operating models within the health care industry ... greater financial efficiency , Deloitte offers a suite ... key business issues impacting efficient cost optimization: labor resource ... , These services facilitate better outcomes and better economics ...
(Date:6/24/2016)... 24, 2016  Global Blood Therapeutics, Inc. (GBT) (NASDAQ: ... novel therapeutics for the treatment of grievous blood-based ... closing of its previously announced underwritten public offering ... public offering price of $18.75 per share. All ... by GBT. GBT estimates net proceeds from the ...
(Date:6/24/2016)... June 24, 2016 Research ... "Structural Electronics 2015-2025: Applications, Technologies, Forecasts" ... In-Mold Electronics, Smart Skin, Structural Health ... Structural electronics involves electronic and/or electrical ... structures, replacing dumb structures such as vehicle bodies ...
Breaking Medicine Technology: