Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Pathway Identified in Human Lymphoma Points Way to New Blood Cancer Treatments

22.11.2012
A pathway called the “Unfolded Protein Response,” or UPR, a cell’s way of responding to unfolded and misfolded proteins, helps tumor cells escape programmed cell death during the development of lymphoma.

Research, led by Lori Hart, Ph.D., research associate and Constantinos Koumenis, Ph.D., associate professor,and research division director in the Department of Radiation Oncology, both from the Perelman School of Medicine, University of Pennsylvania, and Davide Ruggero, Ph.D., associate professor, Department of Urology, University of California, San Francisco, shows for the first time that the UPR is active in patients with human lymphomas and mice genetically bred to develop lymphomas.

Importantly, when the UPR is inactivated, lymphoma cells readily undergo cell death. Their findings appear online in the Journal of Clinical Investigation and will appear in the December 2012 issue.

“The general implications of our work are that components of this pathway may be attractive anti-tumor targets, especially in lymphomas,” says Koumenis. “Indeed, an enzyme called PERK, a kinase that we found to play a central role in UPR, is already being targeted by several groups, in academia and pharmaceutical companies with specific inhibitors.”

The cancer-causing gene c-Myc paradoxically activates both cell proliferation and death. When the cell becomes cancerous, c-Myc–induced death is bypassed, promoting tumor formation. “A critical feature of c-Myc-overexpressing cells is an increased rate of protein synthesis that is essential for Myc’s ability to cause cancer,” says Tom Cunningham, Ph.D., a postdoctoral fellow in the Ruggero lab. “Myc tumor cells use this aberrant production of proteins to block apoptosis and activate the UPR. These cancer cells depend on Myc-induced increases in protein abundance to survive. Therefore, targeting protein synthesis downstream of Myc oncogenic activity may represent a promising new therapeutic window for cancer treatment,” adds Ruggero.

The accumulation of unfolded proteins in the endoplasmic reticulum, an inner cell component where newly made proteins are folded, initiates a stress program, the UPR, to support cell survival. Normally, UPR kicks in when there is an imbalance in the number of proteins that need to be folded and chaperones, specialized proteins that help fold them.

Analysis of mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, the two teams, in collaboration with additional labs in the US and Europe, demonstrated that Myc specifically activated one arm of the UPR, leading to increased cell survival by autophagy.

Autophagy is a survival pathway allowing a cell to recycle damaged proteins when it's under stress and reuse the damaged parts to fuel further growth. Cancer cells might be addicted to autophagy, since this innate response may be a critical means by which the cells survive the nutrient limitation and lack of oxygen commonly found within tumors.

Inhibition of one protein, PERK, in the UPR arm studied, significantly reduced Myc-induced autophagy and tumor formation. What’s more, drug- or genetic-mediated inhibition of autophagy increased Myc-dependent cell death.

“Our findings establish a role for UPR as an enhancer of c-Myc–induced lymphomas and suggest that inhibiting UPR may be particularly effective against cancers characterized by c-Myc overexpression,” says Koumenis. “In this context the UPR essentially acts as one of the cell’s rheostats to counterbalance Myc’s runaway cell replication nature and its pro-cell-death tendencies.”

However, Koumenis indicates that further research is needed on the potential effects of PERK inhibition on normal tissues: “Although data from our lab and other groups suggest that PERK inhibition in tumors grown in animals is feasible, other studies suggest that PERK plays a critical role in the function of secretory tissues such as the pancreas. Carefully testing the effects of new PERK inhibitors in animal models of lymphoma and other malignancies in the next couple of years should address this question and could open the way for new clinical trials with such agents.”

Funding for this research came from the Leukemia and Lymphoma Society Scholar, America Cancer Society grant 121364-PF-11-184-01-TBG; and National Cancer Institute grants R01 CA094214; R01 CA139362; and R01 CA140456.

This work included several laboratories, including those of Alan Diehl and Serge Fuchs, both from Penn; Andrei Thomas-Tikhonenko from CHOP and Penn; and Ian Mills from the Oslo University Hospital.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

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: Automated driving: Steering without limits

OmniSteer project to increase automobiles’ urban maneuverability begins with a € 3.4 million budget

Automobiles increase the mobility of their users. However, their maneuverability is pushed to the limit by cramped inner city conditions. Those who need to...

Im Focus: Microscopy: Nine at one blow

Advance in biomedical imaging: The University of Würzburg's Biocenter has enhanced fluorescence microscopy to label and visualise up to nine different cell structures simultaneously.

Fluorescence microscopy allows researchers to visualise biomolecules in cells. They label the molecules using fluorescent probes, excite them with light and...

Im Focus: NASA's ICESat-2 equipped with unique 3-D manufactured part

NASA's follow-on to the successful ICESat mission will employ a never-before-flown technique for determining the topography of ice sheets and the thickness of sea ice, but that won't be the only first for this mission.

Slated for launch in 2018, NASA's Ice, Cloud and land Elevation Satellite-2 (ICESat-2) also will carry a 3-D printed part made of polyetherketoneketone (PEKK),...

Im Focus: Sinking islands: Does the rise of sea level endanger the Takuu Atoll in the Pacific?

In the last decades, sea level has been rising continuously – about 3.3 mm per year. For reef islands such as the Maldives or the Marshall Islands a sinister picture is being painted evoking the demise of the island states and their cultures. Are the effects of sea-level rise already noticeable on reef islands? Scientists from the ZMT have now answered this question for the Takuu Atoll, a group of Pacific islands, located northeast of Papua New Guinea.

In the last decades, sea level has been rising continuously – about 3.3 mm per year. For reef islands such as the Maldives or the Marshall Islands a sinister...

Im Focus: Energy-saving minicomputers for the ‘Internet of Things’

The ‘Internet of Things’ is growing rapidly. Mobile phones, washing machines and the milk bottle in the fridge: the idea is that minicomputers connected to these will be able to process information, receive and send data. This requires electrical power. Transistors that are capable of switching information with a single electron use far less power than field effect transistors that are commonly used in computers. However, these innovative electronic switches do not yet work at room temperature. Scientists working on the new EU research project ‘Ions4Set’ intend to change this. The program will be launched on February 1. It is coordinated by the Helmholtz-Zentrum Dresden-Rossendorf (HZDR).

“Billions of tiny computers will in future communicate with each other via the Internet or locally. Yet power consumption currently remains a great obstacle”,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

AKL’16: Experience Laser Technology Live in Europe´s Largest Laser Application Center!

02.02.2016 | Event News

From intelligent knee braces to anti-theft backpacks

26.01.2016 | Event News

DATE 2016 Highlighting Automotive and Secure Systems

26.01.2016 | Event News

 
Latest News

A new potential biomarker for cancer imaging

05.02.2016 | Life Sciences

Graphene is strong, but is it tough?

05.02.2016 | Materials Sciences

Tiniest Particles Shrink Before Exploding When Hit With SLAC's X-ray Laser

05.02.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>