Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Adaptation to oxygen deprivation elucidates tumor physiology

08.03.2006


Two new studies in the March Cell Metabolism reveal a survival mechanism by which cells adapt to oxygen starvation by ratcheting down their demand. The mechanism serves to protect against the potentially fatal production of free radicals when oxygen is scarce, one group reported. The findings may also have important implications for understanding the physiology of cancerous tumors, the researchers said, suggesting new combination treatment strategies for fighting the disease.



When the supply of oxygen from the bloodstream fails to meet demand from body tissues--as can occur in the exercising muscle, ischemic hearts, or tumors--hypoxia results, the researchers explained. Cells adapt to low oxygen conditions by activating a "program of gene-expression changes" initiated by so-called hypoxia-inducible factor-1 (HIF-1) transcription factor.

"Over a century ago, Pasteur described that hypoxic cells increase the conversion of glucose [the body’s primary energy source] to lactate, an effect that to date had been primarily attributed to the activities of hypoxia-inducible transcription factors," said study author Chi Dang, from Johns Hopkins University School of Medicine. "The accompanying decrease in cellular respiration in hypoxia was thought to result passively from the paucity of the required oxygen."


The new studies rather reveal that adaptation to hypoxia depends on an active process that serves to inhibit respiration and shunt pyruvate, the lactate precursor, away from mitochondria. Mitochondria are the cells’ "power plants," where food-derived molecules are converted to usable energy via respiration.

"It is a very elegant mechanism," said study author Nicholas Denko of Stanford University School of Medicine. "The cell simply turns off the spigot that sends fuel to the mitochondria."

Both studies found that cells repress mitochondria function and oxygen consumption under low oxygen conditions through the enzyme pyruvate dehydrogenase kinase 1 (PDK1).

Dang’s group showed that, under hypoxic conditions, mouse cells lacking HIF-1 fail to activate PDK1 and undergo cell death (apoptosis) following a dramatic rise in the level of reactive oxygen species (ROS). Forced PDK1 expression in hypoxic cells lacking HIF-1 limited toxic free radical generation and rescued the cells from hypoxia-induced death.

Denko’s team similarly demonstrated in tumor cells that HIF-1 causes a drop in oxygen use, resulting in increased oxygen availability and decreased cell death under low oxygen conditions--findings that might have important implications for cancer therapy, he said.

Indeed, his group found HIF-1 activity made cells more resistant to the antitumor drug tirapazamine (TPZ). They also found that HIF-1-deficient cells grown with limited oxygen exhibit increased sensitivity to TPZ relative to normal cells.

"Recent interest has focused on cytotoxins that target hypoxic cells in tumor microenvironments, such as the drug tirapazamine," said Howard Hughes Medical Institute investigator M. Celeste Simon in a preview. "Because intracellular oxygen concentrations are decreased by mitochondrial oxygen consumption, HIF-1 could protect tumor cells from TPZ-mediated cell death by maintaining intracellular oxygen levels."

While HIF-1 inhibition in hypoxic tumor cells should have multiple therapeutic benefits, Simon added, "the use of HIF-1 inhibitors in conjunction with other treatments has to be carefully evaluated for the most effective combination and sequence of drug delivery."

Heidi Hardman | EurekAlert!
Further information:
http://www.cellmetabolism.org

More articles from Studies and Analyses:

nachricht New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)

nachricht Reusable carbon nanotubes could be the water filter of the future, says RIT study
30.03.2017 | Rochester Institute of Technology

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

NASA's Fermi catches gamma-ray flashes from tropical storms

25.04.2017 | Physics and Astronomy

Researchers invent process to make sustainable rubber, plastics

25.04.2017 | Materials Sciences

Transfecting cells gently – the LZH presents a GNOME prototype at the Labvolution 2017

25.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>