PHILADELPHIA â€” A pathway called the â€śUnfolded Protein Response,â€ť or UPR, a cellâ€™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.
â€śThe general implications of our work are that components of this pathway may be attractive anti-tumor targets, especially in lymphomas,â€ť says Koumenis. â€śIndeed, 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.â€ť
The cancer-causing gene c-Myc paradoxically activates both cell proliferation and death. When the cell becomes cancerous, c-Mycâ€“induced death is bypassed, promoting tumor formation. â€śA critical feature of c-Myc-overexpressing cells is an increased rate of protein synthesis that is essential for Mycâ€™s ability to cause cancer,â€ť says Tom Cunningham, Ph.D., a postdoctoral fellow in the Ruggero lab. â€śMyc 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,â€ť 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.
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