Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers find new way to trigger self-destruction of certain cancer cells

20.06.2003


Discovery could lead to new drug therapy for some childhood cancers



Investigators at St. Jude Children’s Research Hospital have discovered a previously unrecognized way that certain types of cancer cells can be forced to activate a self-destruction program called apoptosis.

The finding suggests that drugs designed to activate apoptosis might be effective anti-cancer therapies. This strategy would target specific molecules in the cancer cell rather than rely on chemotherapy, which has serious side effects that degrade quality of life. The research is published in the June 20 issue of Molecular Cell.


The St. Jude team stimulated apoptosis by treating cancer cells with a drug called rapamycin, which blocks the action of a protein called mTOR. This protein stimulates a biochemical pathway that leads to increased production of proteins essential for cell proliferation. Blocking mTOR with rapamycin leaves the cell unable to make these critical proteins.

Blocking the activity of mTOR with rapamycin triggers a biochemical pathway called the JNK cascade in cells that lack a gene called p53, according to Peter Houghton, Ph.D., chair of the St. Jude Department of Molecular Pharmacology. Since p53 is mutated and inactive in about half of all types of cancer, blocking mTOR and activating apoptosis in cells with mutated p53 has potentially wide application. Houghton is senior author of the paper reporting these results.

"Shutting down synthesis of proteins essential for cell proliferation by blocking mTOR sends the cell into a crisis," Houghton said. "The cell activates a protein called ASK1, which is at the top of the JNK cascade. ASK1 then sets off the JNK cascade and causes the cells that lack p53 to self-destruct."

In cells that have a functional p53 gene, (e.g., normal cells), a protein called p21 is expressed and--in the presence of rapamycin--binds to ASK1 and inactivates it. This prevents the cell from undergoing apoptosis.

The investigators also found that the stress caused by rapamycin requires the presence of a protein called 4E-BP1. This protein stops the cell from using use some types of mRNA (the "decoded" form of DNA) to make proteins, including survival factors. 4E-BP1 is normally held in check by mTOR; so the cell continues to use mRNA to make proteins that are essential for proliferation. However, when rapamycin blocks mTOR, 4E-BP1 is free to put the brakes on.

In cells lacking p53, activation of the JNK cascade by rapamycin occurs so quickly that it might not be caused directly by the inhibition of protein synthesis.

"Right now, we don’t know exactly what sends the cell into crisis after rapamycin blocks mTOR," Houghton said. "Further study is needed to determine what the link is between shutting down production of specific proteins and the cellular crisis that prompts cells to undergo apoptosis."

The strategy of using rapamycin to block mTOR and activate ASK1 could be thwarted by another survival factor, called IGF-I.

"IGF-I prevents rapamycin from activating ASK1, and therefore shuts down the pathway that leads to apoptosis," Houghton said. "So any drug therapy that targets mTOR with the intent of inducing cell death should also include a drug that targets IGF-I signaling. That double hit would leave the cancer cell no choice but to self-destruct."

For this research, Houghton’s team used Rh30 cells--rhabdomyosarcoma cells lacking p53. The team showed that rapamycin caused sustained activation of the JNK cascade; and that exposure of Rh30 cells to IGF-I completed blocked the activation of c-Jun, a critical protein in the JNK cascade that is activated by rapamycin.

The team also showed that the Rh30 cells could be thrown into a crisis by starving them of amino acids, the building blocks of proteins. This stress required the presence of 4E-BP1 and activation of ASK1. Rh30 cells with rapamycin-resistant mTOR did not respond to the drug by triggering apoptosis. This was strong evidence that rapamycin had its effect on apoptosis by blocking mTOR.

St. Jude investigators are now planning clinical trials of two drugs that are rapamycin analogs (slight chemical modifications of rapamycin). The drugs, CCI779 (Wyeth-Ayerst) and RAD001 (Novartis), will be investigated for safety. Clinical trials will investigate their effectiveness in treating neuroblastoma, a cancer of specialized nerve cells involved in the development of the nervous system and other tissues.

Other authors of the paper include Shile Huang, Lili Shu, Michael B. Dilling, John Easton, Franklin C. Harwood (St. Jude) and Hidenori Ichijo (Tokyo Medical and Dental University; Tokyo, Japan).

Contact: Bonnie Cameron, bonnie.cameron@stjude.org

Bonnie Cameron | EurekAlert!
Further information:
http://www.stjude.org

More articles from Health and Medicine:

nachricht Oxygen can wake up dormant bacteria for antibiotic attacks
08.12.2016 | Penn State

nachricht NTU scientists build new ultrasound device using 3-D printing technology
07.12.2016 | Nanyang Technological University

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: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Scientists track chemical and structural evolution of catalytic nanoparticles in 3-D

08.12.2016 | Materials Sciences

Decoding cement's shape promises greener concrete

08.12.2016 | Materials Sciences

Will Earth still exist 5 billion years from now?

08.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>