Enzyme that flips switch on cells' sugar cravings could be anti-cancer target
Cancer cells' metabolic preference is known as the "Warburg effect," after 1931 Nobel Prize winner Otto Warburg. Credit: Wikipedia commons
Cancer cells tend to take up more glucose than healthy cells, and researchers are increasingly interested in exploiting this tendency with drugs that target cancer cells' altered metabolism.
Cancer cells' sugar cravings arise partly because they turn off their mitochondria, power sources that burn glucose efficiently, in favor of a more inefficient mode of using glucose. They benefit because the byproducts can be used as building blocks for fast-growing cells.
Scientists at Winship Cancer Institute of Emory University have shown that many types of cancer cells flip a switch that diverts glucose away from mitochondria. Their findings suggest that tyrosine kinases, enzymes that drive the growth of several types of cancer, play a greater role in mitochondria than previously recognized.
The results also highlight the enzyme PDHK (pyruvate dehydrogenase kinase) as an important point of control for cancer cell metabolism.
The results were published online Thursday by the journal Molecular Cell.
This video is not supported by your browser at this time."We and others have shown that PDHK is upregulated in several types of human cancer, and our findings demonstrate a new way that PDHK activity is enhanced in cancer cells," says Jing Chen, PhD, associate professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. "PDHK is a very attractive target for anticancer therapy because of its role in regulating cancer metabolism."
Chen and Sumin Kang, PhD, assistant professor of hematology and medical oncology at Emory University School of Medicine, are co-corresponding authors. Postdoctoral fellows Taro Hitosugi, Jun Fan and Tae-Wook Chung are co-first authors of the paper. Co-authors at Emory include Georgia Chen, PhD, Sagar Lonial, MD, Haian Fu, PhD, and Fadlo Khuri, MD. Collaborators at Yale University, Novartis and Cell Signaling Technology contributed to the paper.
Chen and his colleagues started out studying the tyrosine kinase FGFR1, which is activated in several types of cancer. Tyrosine kinases attach a phosphate to other proteins, making them more or less active. They found that FGFR1 activates the enzyme PDHK, which has a gatekeeper function for mitochondria.
"We used FGFR1 as a platform to look at how metabolic enzymes are modified by oncogenic tyrosine kinases," Chen says. "We discovered that several oncogenic tyrosine kinases activate PDHK, and we found that many of those tyrosine kinases are found within mitochondria."
This was a surprise because tyrosine kinases are usually thought to drive growth by being active next to the cell membrane, Chen says.
Introducing a form of PDHK that is insensitive to tyrosine kinases into human cancer cells forces the cells to grow more slowly and form smaller tumors in mice, they found. This indicates that PDHK could be a target for drugs that specifically target cancer cells' altered metabolism.
The experimental drug dichloroacetate (DCA), which inactivates PDHK, is being used in new clinical trials for cancer. Chen is collaborating with Haian Fu, professor of pharmacology and director of the Emory Chemical Biology Discovery Center, to find other, more potent inhibitors of PDHK.
More information: T. Hitosugi et al. Tyrosine Phosphorylation of Mitochondrial Pyruvate Dehydrogenase Kinase 1 Is Important for Cancer Metabolism. Mol Cell (2011). www.cell.com/molecular-cell/
Provided by Emory University
- Cancers' sweet tooth may be weakness Nov 18, 2009 | not rated yet | 0
- Researchers identify signaling protein for multiple myeloma Sep 10, 2007 | not rated yet | 0
- Enzyme is Possible New Therapy Target for Head and Neck Cancer Mar 19, 2010 | not rated yet | 0
- Combination therapies for drug-resistant cancers Oct 10, 2011 | not rated yet | 0
- Separating a cancer prevention drug from heart disease risk Sep 13, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
How can there be villous adenoma in colon, if there are no villi there
14 hours ago As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
- More from Physics Forums - Medical Sciences
More news stories
(HealthDay)—The American Cancer Society, which is celebrating on Wednesday a century of fighting a disease once viewed as a death sentence, is making a pledge to put itself out of business.
Cancer 4 hours ago | not rated yet | 0
National Lung Screening Trial (NLST) investigators also conclude that the 20 percent reduction in lung cancer mortality with low-dose computed tomography (LDCT) versus chest X-ray (CXR) screening previously reported in the ...
Cancer 4 hours ago | not rated yet | 0
Researchers have developed a new drug delivery system that allows inhalation of chemotherapeutic drugs to help treat lung cancer, and in laboratory and animal tests it appears to reduce the systemic damage ...
Cancer 7 hours ago | not rated yet | 0 |
When turned on, the gene p53 turns off cancer. However, when existing drugs boost p53, only a few tumors die – the rest resist the challenge. A study published in the journal Cell Reports shows how: tumors that live even i ...
Cancer 8 hours ago | not rated yet | 0 |
Study leader, Professor John Mathews from the University of Melbourne said this small increase in cancer risk must be weighed against the undoubted benefits from CT scans in diagnosing and monitoring disease.
Cancer 12 hours ago | not rated yet | 0
Swiss scientists reveal the mechanism responsible for aging hidden deep within mitochondria—and dramatically slow it down in worms by administering antibiotics to the young.
8 hours ago | 4.8 / 5 (4) | 0 |
Researchers from Queen Mary, University of London have led the largest sequencing study of human disease to date, investigating the genetic basis of six autoimmune diseases.
8 hours ago | not rated yet | 0 |
Until now, little was scientifically known about the human potential to cultivate compassion—the emotional state of caring for people who are suffering in a way that motivates altruistic behavior.
5 hours ago | 5 / 5 (1) | 2 |
(HealthDay)—Migraines and depression can each cause a great deal of suffering, but new research indicates the combination of the two may be linked to something else entirely—a smaller brain.
5 hours ago | 5 / 5 (1) | 0 |
A new approach for immunizing against influenza elicited a more potent immune response and broader protection than the currently licensed seasonal influenza vaccines when tested in mice and ferrets. The vaccine ...
6 hours ago | not rated yet | 0 |
In a series of lab experiments designed to unravel the workings of a key enzyme widely considered a possible trigger of rheumatoid arthritis, researchers at Johns Hopkins have found that in the most severe ...
7 hours ago | 5 / 5 (1) | 0 |