Cancer cells typically avoid death by hijacking molecular chaperones that guide and protect the proteins that ensure normal cellular function and then tricking them into helping mutated versions of those proteins stay alive, says Dr. Ahmed Chadli, a researcher in the Molecular Chaperone Program at the GRU Cancer Center and senior author of the study named the Journal of Biological Chemistry's Paper of the Week.
Drug development has focused on the chaperone Hsp90 (heat shock protein 90) because it plays a key role in assisting mutated proteins, making it an attractive cancer drug target. However, the clinical efficacy of Hsp90 inhibitors has been disappointing. Most current small molecules targeting Hsp90 have inadvertently resulted in the expression of proteins that protect cancer cells from programmed cell death and compromise the Hsp90 inhibitors in the clinic.
In this study, however, Chaitanya Patwardhan, a graduate student in Dr. Chadli's lab, found that gedunin, an Indian plant compound, attacks a co-chaperone, or helper protein, of Hsp90 called p23.
"This compound binds directly to p23, leading to inactivation of the Hsp90 machine—without production of anti-apoptotic proteins—thus killing cancer cells," said Dr. Chadli. "The idea here is that this will open a door for new ways of targeting Hsp90 by targeting its helper proteins, which may be used in combination with established Hsp90 inhibitors that are ongoing clinical trials. In the future, this research could have applications in drug development for hormone-dependent cancers, including breast, prostate and endometrial cancers."
"One of the major areas of scientific emphasis of the GRU Cancer Center is to develop therapeutic approaches to cancer targeting specific molecules within the cancer cell, including chaperones," said Dr. Samir N. Khleif, Director of the GRU Cancer Center. "This finding is an important piece of the puzzle, bringing us closer to our goal of helping patients with cancer."
Along with Patwardhan, the study was also authored by Dr. Abdul Fauq, Mayo Clinic College of Medicine; Laura B. Peterson and Dr. Brian S.J. Blagg, both of the University of Kansas; and Dr. Charles Miller, Tulane University School of Public Health and Tropical Medicine.
Dr. Chadli's lab is also the recipient of a National Institutes of Health R01 grant to look for new molecules targeting the Hsp90 machine.
Only the top 2 percent of the 6,600 manuscripts annually reviewed in terms of significance and overall importance, by the JBC are ranked as Papers of the Week. The study will also be the focus of an upcoming JBC podcast.
Danielle Moores | EurekAlert!
During HIV infection, antibody can block B cells from fighting pathogens
14.08.2018 | NIH/National Institute of Allergy and Infectious Diseases
First study on physical properties of giant cancer cells may inform new treatments
14.08.2018 | Brown University
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.
Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...
Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur
What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...
The quality of materials often depends on the manufacturing process. In casting and welding, for example, the rate at which melts solidify and the resulting microstructure of the alloy is important. With metallic foams as well, it depends on exactly how the foaming process takes place. To understand these processes fully requires fast sensing capability. The fastest 3D tomographic images to date have now been achieved at the BESSY II X-ray source operated by the Helmholtz-Zentrum Berlin.
Dr. Francisco Garcia-Moreno and his team have designed a turntable that rotates ultra-stably about its axis at a constant rotational speed. This really depends...
08.08.2018 | Event News
27.07.2018 | Event News
25.07.2018 | Event News
14.08.2018 | Information Technology
14.08.2018 | Life Sciences
14.08.2018 | Life Sciences