Cancerous tumors are wildly unfavorable environments. Struggling for oxygen and nutrients while being bombarded by the body’s defense systems, tumor cells in fact require sophisticated adaptations to survive and grow. For decades, scientists have sought ways to circumvent these adaptations to destroy cancer.
Now, researchers at the University of Massachusetts Medical School (UMMS), have defined a method to target and kill cancer’s “chaperone”—a protein that promotes tumor cell stability and survival—without damaging healthy cells nearby.
In “Regulation of Tumor Cell Mitochondrial Homeostasis by an Organelle-Specific Hsp90 Chaperone Network,” published in the October 19 issue of Cell, Dario C. Altieri, MD, the Eleanor Eustis Farrington Chair in Cancer Research and professor and chair of cancer biology, and colleagues at UMMS, identify a new pathway by which cancer cells grow and survive—and provide a clear blueprint for the design and production of a novel class of anticancer agents aimed squarely at that pathway.
While previous research has demonstrated that a class of proteins known as molecular chaperones promote tumor cell survival, the specific way in which the proteins achieve this has not been well understood. And although inhibitors of a specific chaperone known as heat shock protein 90 (Hsp90) have been studied for the treatment of cancer, progress has been questionable. In this current research, Dr. Altieri and colleagues sought to both define the mechanism by which Hsp90 leads to tumor cell stability and survival, and understand why general suppression of Hsp90 has not been as successful in clinical trials.
Notably, they found a very abundant pool of Hsp90 (and its related molecule TRAP-1) in the mitochondria of tumor cells. Mitochondria are organelles that produce a cell’s energy, but also play a key role in cell death. Indeed, many current drugs and treatments work by damaging the mitochondria. Data obtained by Altieri and colleagues indicate that Hsp90 and TRAP-1 protect mitochondria in tumor cells from fulfilling their role in cell death. Significantly, the increased levels of Hsp90 and TRAP-1 were found only in the mitochondria of tumor cells—not in those of normal cells.
“We have identified this mitochondrial accumulation of Hsp90 and TRAP-1 as a critical adaptive mechanism that makes cancer cells less susceptible to the unfavorable environment of tumors, and to various anticancer agents,” Altieri explained.
This new understanding of the sub-cellular location of Hsp90 and TRAP-1 in the mitochondria also answers the question as to why the current Hsp90 inhibitors—which do not penetrate the mitochondria—are not as effective as hoped in the clinic. In this study, Altieri and colleagues synthesized a new compound, modifying an existing Hsp90 inhibitor so that it was able to reach the mitochondria. When the inhibitors were able to penetrate the mitochondria, they were able to eliminate the protective function of Hsp90, and induce massive tumor cell death. Notably, because this accumulation of Hsp90 and TRAP-1 only occurs in tumor cells, drugs conceived to target Hsp90 would largely spare normal cells, minimizing or even nullifying the dramatic side effects that plague many current cancer treatments.
“This is an important discovery that opens the door to the design of a completely new class of anticancer agents,” Altieri explained. “It really turns the tables on a field that has been explored with only partial success. We can now take a class of drugs and make them better and more efficacious by engineering them to accumulate in the mitochondria.”
Kelly Bishop | EurekAlert!
First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife
Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
25.10.2016 | Earth Sciences
25.10.2016 | Power and Electrical Engineering
25.10.2016 | Process Engineering