WASHINGTON (July 6, 2015) -- The investigation of a simple protein has uncovered its uniquely complicated role in the spread of the childhood cancer, osteosarcoma. It turns out the protein, called ezrin, acts like an air traffic controller, coordinating multiple functions within a cancer cell and allowing it to endure stress conditions encountered during metastasis.
It's been known that ezrin is a key regulator of osteosarcoma's spread to the lungs, but its mechanism was not known. Osteosarcoma is a tumor of bone that afflicts children, adolescents and young adults. In most cases, the tumor is localized in the extremities and can be completely removed by surgery or amputation.
"The main cause of death in osteosarcoma patients is not the tumor on their limbs, but the failure of their lungs when the cancer spreads there," explains Aykut Üren, MD, professor of oncology at Georgetown Lombardi Comprehensive Cancer Center.
Üren and his colleagues have developed molecules that block ezrin's function and prevent osteosarcoma spread in mouse models. In an attempt to explain the molecular mechanisms underlying ezrin-mediated cancer metastasis, the researchers discovered this previously unrecognized role for ezrin. Their finding is published online today in the journal Molecular and Cellular Biology.
"Conventionally ezrin was believed to be functioning only on the inner surface of cancer cells," Üren says, "but our new discovery indicates that ezrin may operate deeper in the core of the cell and regulate expression of critical genes that are important for cancer's spread."
The scientists say that ezrin functions in a new capacity that is unusual for its family of proteins. They found that ezrin's unusual interaction with another protein called DDX3 results in modulation of genes that give cancer cells an edge in surviving harsh conditions.
"Knowing exactly how ezrin works will help our team develop the ezrin-targeting small molecules as potential new drugs to prevent the spread of cancer cells to lungs in osteosarcoma patients," Uren says.
"Implications of our findings go beyond cancer research," says the study's first author Haydar Çelik, PhD. "Because this work suggests a new molecular mechanism on how ezrin is involved in the regulation of mRNA translation, these observations may provide important clues for scientists investigating how viruses enter and replicate in human cells too."
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Additional Georgetown co-authors include Kamal P. Sajwan, Saravana P. Selvanathan, PhD, Benjamin J. Marsh, Amrita V. Pai, Yasemin Saygideger Kont, MD, Jenny Han, Tsion Z. Minas, Said Rahim, PhD, Hayriye Verda Erkizan, PhD and Jeffrey A. Toretsky, MD.
A Department of Defense Synergistic Idea Development Award (W81XWH-10-1-0137) funded the study.
Georgetown University has filed a patent application for using NSC305787 and related compounds to inhibit ezrin function and for the treatment of cancer. Üren and Toretsky are listed as inventors.
About Georgetown Lombardi Comprehensive Cancer Center
Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and MedStar Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Georgetown Lombardi is one of only 41 comprehensive cancer centers in the nation, as designated by the National Cancer Institute (grant #P30 CA051008), and the only one in the Washington, DC area. For more information, go to http://lombardi.georgetown.edu.
About Georgetown University Medical Center
Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health.
Journal
Molecular and Cellular Biology