Navigation Links
Pathway identified in human lymphoma points way to new blood cancer treatments

PHILADELPHIA 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-Mycinduced 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-Mycinduced 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."

Contact: Karen Kreeger
University of Pennsylvania School of Medicine

Related medicine news :

1. Cellular pathway linked to diabetes, heart disease
2. Unusual protein helps regulate key cell communication pathway
3. Mutant Kras drives pancreatic cancer maintenance via metabolic pathways
4. Breast stem-cell research: Receptor teamwork is required and a new pathway may be involved
5. VCU researchers identify changes in cholesterol metabolic pathways
6. Researchers determine pathway for origin of most common form of brain and spinal cord tumor
7. Inhibiting Hedgehog signaling pathway may improve pancreatic cancer treatment
8. Global Energy Assessment identifies pathways to a sustainable energy future
9. Grb2 holds powerful molecular signaling pathway in check
10. Researchers block pathway to cancer cell replication
11. Discovery explains how cellular pathways converge to regulate food intake and body weight
Post Your Comments:
Related Image:
Pathway identified in human lymphoma points way to new blood cancer treatments
(Date:6/24/2016)... ... June 24, 2016 , ... June 19, 2016 is World Sickle Cell ... pain and the benefits of holistic treatments, Serenity Recovery Center of Marne, ... Cell Disease. , Sickle Cell Disease (SCD) is a disorder of the red blood ...
(Date:6/24/2016)... ... June 24, 2016 , ... ... Sessions in Dallas that it will receive two significant new grants to support ... as PHA marked its 25th anniversary by recognizing patients, medical professionals and scientists ...
(Date:6/24/2016)... ... June 24, 2016 , ... Dr. Amanda Cheng, an ... Dr. Cheng has extensive experience with all areas of orthodontics, including robotic Suresmile ... orthodontics. , Micro-osteoperforation is a revolutionary adjunct to orthodontic treatment. It can ...
(Date:6/24/2016)... ... 24, 2016 , ... Topical BioMedics, Inc, makers of Topricin and MyPainAway Pain Relief Products, join ... wage raise to $12 an hour by 2020 and then adjusting it yearly to increase ... of the minimum wage, assure the wage floor does not erode again, and make future ...
(Date:6/24/2016)... Georgia (PRWEB) , ... June 24, 2016 , ... ... awards today at the Clinical Decision Making in Emergency Medicine conference in Ponte ... have authored journal articles published in Emergency Medicine Practice and Pediatric ...
Breaking Medicine News(10 mins):
(Date:6/23/2016)... , June 23, 2016 Research and ... News Issue 52" report to their offering. ... influenza treatment creates a favourable commercial environment for MedImmune to ... patient base that will serve to drive considerable growth for ... would serve to cap sales considerably, but development is still ...
(Date:6/23/2016)... , June 23, 2016  Astellas today announced the establishment of Astellas Farma Colombia (AFC), a new affiliate ... in Latin America . ... ... ... ...
(Date:6/23/2016)... June 23, 2016 Research and ... Procedure Volumes: Global Analysis (United States, China, Japan, Brazil, ... report to their offering. ... for healthcare business planners, provides surgical procedure volume data ... trends with an in-depth analysis of growth drivers and ...
Breaking Medicine Technology: