Photo: Hye-Ra Lee, Ph.D.
Researchers at the
University of Southern California have identified two molecules that
may be more effective cancer killers than are currently available on
the market.
The peptides, molecules derived from a cancer-causing virus, target an
enzyme in cancerous cells that regulates a widely researched tumor
suppressor protein known as p53. The peptides inhibit the enzyme,
causing p53 levels in cancer cells to rise, which leads to cell death.
Lymphoma tumors in mice injected with the two peptides showed marked
regression with no significant weight-loss or gross abnormalities.
The discovery is detailed in the journal
Nature Structural & Molecular Biology,
which posted online on Sunday, Nov. 6.
HAUSP, or herpesvirus-associated ubiquitin specific protease, is an
enzyme that cleaves the normally occurring protein ubiquitin from
substrates like p53. In a healthy environment, ubiquitin binds to a
substrate, causing it to degrade and die.
“Given the mounting evidence that HAUSP serves as a pivotal component
regulating p53 protein levels, the inhibition of HAUSP should have the
benefit to fully activate p53,” said Hye-Ra Lee, Ph.D., the study’s
first author and a research fellow in the
Department
of Molecular Microbiology & Immunology at the
Keck School of Medicine of
USC.
Using co-crystal structural analysis, Lee and her colleagues found a
tight, “belt-type” interaction between HAUSP and a viral protein that
causes Kaposi’s sarcoma and lymphoma. The peptides derived from this
viral protein bind 200 times more strongly to HAUSP than p53, making
them ideal HAUSP inhibitors. The researchers found that the peptides
comprehensively prevented HAUSP from cleaving ubiquitin, allowing p53
levels to rise — thereby representing potential new chemotherapeutic
molecules that can be used for anti-cancer therapies.
New research is under way with
Nouri Neamati,
Ph.D., associate professor of pharmacology and pharmaceutical
sciences in the
USC School of
Pharmacy, to find small molecules that mimic the peptides. The
peptides and other small molecules are being tested on different
cancers.
“Significant advances in scientific understanding often come at the
intersection of independent lines of research from different
disciplines, for instance, structure and virus study. Time after time,
viruses are teaching us,” said
Jae Jung, Ph.D.,
the study’s principal investigator and chairman of the Department of
Molecular Microbiology & Immunology at the Keck School of Medicine.
Authors of the study include researchers from the Korea Research
Institute of Bioscience and Biotechnology, Korea Advanced Institute of
Science and Technology, Korea Basic Science Institute, Korea
University, University of Science and Technology (Korea), and
Ludwig-Maximilians-Universität München. Funding came from the National
Institute of Health and National Research Foundation of Korea.