Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Chemotherapy Resistance: Checkpoint Protein Provides Armor Against Cancer Drugs

31.08.2009
Cell cycle checkpoints act like molecular tripwires for damaged cells, forcing them to pause and take stock. Leave the tripwire in place for too long, though, and cancer cells will press on regardless, making them resistant to the lethal effects of certain types of chemotherapy, according to researchers at the Salk Institute for Biological Studies.

Their findings, published in the Aug. 28 issue of Molecular Cell, help explain how the checkpoint exit is delayed in some cancer cells, helping them to recover and resume dividing after treatment with DNA-damaging cancer drugs.

“A lot of progress has been made in understanding the molecular details of checkpoint activation,” says senior author Tony Hunter, Ph.D., a professor in the Molecular and Cell Biology Laboratory, “but checkpoint termination, which is essential for the resumption of cell cycle progression, is less well understood.”

The Salk researchers say that a better understanding of this crucial process may allow them to develop biological markers that predict clinical resistance to chemotherapy and to design cancer drugs with fewer side effects by exploiting the molecular mechanism underlying the checkpoint exit.

“If we could screen tumors for markers of chemo-resistance, we could then adjust the treatment accordingly,” hopes first author You-Wei Zhang, Ph.D., formerly a postdoctoral researcher in Hunter’s lab and now an assistant professor at Case Western Reserve University in Cleveland, Ohio.

In response to DNA damage and blocked replication—the process that copies DNA—eukaryotes activate the DNA damage checkpoint pathway, which stops the cell cycle, buying time to repair damage and recover from stalled or collapsed replication forks. If not repaired, these errors can either kill a cell when it attempts to divide or lead to genomic instability and eventually cancer.

A key role in this process is played by the checkpoint protein Chk1, which responds to stressful conditions induced by hypoxia, DNA damage–inducing cancer drugs, and irradiation. These same conditions set the protein up for eventual degradation. But how the cellular protein degradation machinery knows that it is time to dispose of activated Chk1 was unclear.

In his experiments, Zhang discovered that activation of Chk1 exposes a so-called degron, a specific string of amino acids that attracts the attention of a protein known as Fbx6, short for F box protein 6. Fbx6 in turn brings in an enzyme complex that flags Chk1 proteins for degradation, allowing the cell to get rid of the activated checkpoint protein. Once Chk1 is eliminated, cells will resume the cell cycle progression, or, in the prolonged presence of replication stress, undergo programmed cell death. Yet some cancer cells keep dividing even in the presence of irreparable damage.

“Camptothecins are FDA-approved cancer drugs that induce replication stress and stop cancer cells dividing, but their clinical antitumor activity is very limited by the relatively rapid emergence of drug resistance, and the mechanisms are poorly understood,” says Hunter. “We wondered whether defects in the Chk1 destruction machinery might allow cells to ignore the effects of camptothecin and similar drugs used for chemotherapy.”

When Zhang checked cultured cancer cell lines and breast cancer tissue, he found that low levels of Fbx6 predicted high levels of Chk1 and vice versa. But most importantly, he was able to demonstrate that two of the three most camptothecin-resistant cancer cell lines in the cancer cell line panel available through the National Cancer Institute displayed significant defects in camptothecin-induced Chk1 degradation, which seemed to be caused by very low levels of Fbx6 expression.

“Chk1 and Fbx6 clearly play an important role for the regulation of the response to chemotherapy,” he says. “One day, they could become an important prognostic marker that predicts patients’ responsiveness to drugs such as irinotecan, platinum compounds, and gemcitabine, while Chk1 inhibitors might increase tumor cells’ sensitivity to these drugs.” Such a combination therapy could overcome clinical resistance or allow doctors to reduce the amount of administered drug, thereby reducing the often debilitating side effects.

Researchers who contributed to the work include John Brognard, Ph.D., Zhongsheng You, Ph.D., and Aaron Aslanian, Ph.D., in the Molecular and Cellular Biology Laboratory; Chris Coughlin, Ph.D., and Robert T. Abraham, Ph.D., at Wyeth Oncology Discovery in Pearl River, NY; Marisa Dolled-Filhart, Ph.D., at HistoRx Inc., New Haven, CT; and Gerard Manning, Ph.D., director of the Razavi-Newman Center for Bioinformatics at the Salk Institute.

About the Salk Institute for Biological Studies

The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes, and cardiovascular disorders by studying neuroscience, genetics, cell and plant biology, and related disciplines.

Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.

Mauricio Minotta | Newswise Science News
Further information:
http://www.salk.edu

More articles from Life Sciences:

nachricht What the world's tiniest 'monster truck' reveals
23.08.2017 | American Chemical Society

nachricht Treating arthritis with algae
23.08.2017 | Empa - Eidgenössische Materialprüfungs- und Forschungsanstalt

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

What the world's tiniest 'monster truck' reveals

23.08.2017 | Life Sciences

Treating arthritis with algae

23.08.2017 | Life Sciences

Witnessing turbulent motion in the atmosphere of a distant star

23.08.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>