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

More articles from Health and Medicine:

nachricht On track to heal leukaemia
18.01.2017 | Universitätsspital Bern

nachricht Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania

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: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

A big nano boost for solar cells

18.01.2017 | Power and Electrical Engineering

Glass's off-kilter harmonies

18.01.2017 | Materials Sciences

Toward a 'smart' patch that automatically delivers insulin when needed

18.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>