In the July 1 issue of Cancer Research, the scientists say glucose-regulated protein 78 (GRP78), activated as breast cells undergo stress induced by the agents tamoxifen and fulvestrant, turns off apoptosis, a cell death response, and turns on autophagy. In autophagy, the cell "eats" and digests components within the cell body that have been harmed by the drugs, thus providing a blast of nutrients needed to maintain life.
The finding suggests that a novel agent that inhibits GRP78 might provide a solution for the tens of thousands of women who develop resistance to anti-estrogen drugs. While more than 70 percent of breast cancers express estrogen receptors that fuel growth of cancer, about one-third of these cases fail to be cured by therapies that target this receptor.
"Since GRP78 plays such an important role in drug resistance, it would be of great benefit to develop agents that target this protein," says the study's lead author, Katherine Cook, Ph.D., a postdoctoral investigator in the lab of Robert Clarke, Ph.D., D.Sc., professor of oncology and Dean for Research at Georgetown University Medical Center. Clarke is the study's senior author.
She adds that several GRP78 inhibitors have already been developed and are already being tested, but not yet at the level of human clinical trials.
The study is not only the first to show that GRP78 is a regulator of resistance to tamoxifen and fulvestrant, it is also the first to reveal the mechanism by which GRP78 directly controls autophagy, says Clarke.
"Why estrogen-receptor positive breast tumors fail to respond, or respond initially and progress upon acquiring resistance to these agents, has been largely unknown, " he says. "The novel signaling that we have uncovered could have high translational impact and bring a new and important perspective to the molecular crosstalk between cell stress, apoptosis, and autophagy."
This research is a continuation of a string of studies on anti-estrogen resistance by Clarke, Cook, and their collaborators at Georgetown.
A paper published March 15 in Cancer Research, for example, described how a program known as the "unfolded protein response" or UPR, is activated in breast cells treated with the therapies once these cells sense stress. This response is activated when there is an accumulation of unfolded or misfolded proteins within the cell.
"Since cancers often grow rapidly, tumors may lack enough energy to properly fold proteins into the correct orientation. These misfolded proteins accumulate in the cell and trigger UPR," says Cook. "In normal cells, UPR is protective and if the stimuli lasts for an extended period of time UPR becomes pro-death. But we have found cancers use the UPR to promote survival."
In this study, the scientists zeroed in on GRP78 as the master regulator of UPR, thus promoting anti-estrogen resistance. It does this by preventing stressed cells to initiate programmed cell death, and by stimulating autophagy, which clears cells of the misfolded proteins while providing beneficial nutrition to the cell.
When the scientists inhibited GRP78 in anti-estrogen resistant cells, they promoted cell death and inhibited autophagy, resulting in increased numbers of dead cells.
They also found that GRP78 does not play a role in breast cancers that never responded to anti-estrogen therapy, indicating that initial resistance and acquired resistance represent separate biological phenomenon. "This observation is consistent with the emerging concept that acquired resistance may be an adaptive response," Cook says.
She also notes that elevated GRP78 has been found in different cancer types, in addition to breast cancer, and in resistance to several different chemotherapy treatments.
"The basic principle we establish of using GRP78 to integrate the cellular functions of apoptosis and autophagy raises the provocative question that this signaling may be widely applicable and represent a major stress response," Cook says.
Other investigators who contributed to the research are Ayesha N. Shajahan Ph.D., Anni Wärri Ph.D., Lu Jin M.S., and Leena A. Hilakivi-Clarke Ph.D., of the department of oncology at Georgetown Lombardi Comprehensive Medical Center. The authors report having no personal financial interests related to the study. This research was supported by NCI grants Clarke (R01-CA131465 and U54-CA149147). Cook was supported by a National Institutes of Health (NIH)/National Cancer Institute (NCI) training grant (5-T32-CA009686), and she is a recipient of a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship (BC112023).About Georgetown Lombardi Comprehensive Cancer Center
Karen Mallet | EurekAlert!
Biophysicists reveal how optogenetic tool works
29.05.2020 | Moscow Institute of Physics and Technology
Mapping immune cells in brain tumors
29.05.2020 | University of Zurich
In living cells, enzymes drive biochemical metabolic processes enabling reactions to take place efficiently. It is this very ability which allows them to be used as catalysts in biotechnology, for example to create chemical products such as pharmaceutics. Researchers now identified an enzyme that, when illuminated with blue light, becomes catalytically active and initiates a reaction that was previously unknown in enzymatics. The study was published in "Nature Communications".
Enzymes: they are the central drivers for biochemical metabolic processes in every living cell, enabling reactions to take place efficiently. It is this very...
Early detection of tumors is extremely important in treating cancer. A new technique developed by researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from normal tissue. The work is published May 25 in the journal Nature Nanotechnology.
researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from...
Microelectronics as a key technology enables numerous innovations in the field of intelligent medical technology. The Fraunhofer Institute for Biomedical Engineering IBMT coordinates the BMBF cooperative project "I-call" realizing the first electronic system for ultrasound-based, safe and interference-resistant data transmission between implants in the human body.
When microelectronic systems are used for medical applications, they have to meet high requirements in terms of biocompatibility, reliability, energy...
Thomas Heine, Professor of Theoretical Chemistry at TU Dresden, together with his team, first predicted a topological 2D polymer in 2019. Only one year later, an international team led by Italian researchers was able to synthesize these materials and experimentally prove their topological properties. For the renowned journal Nature Materials, this was the occasion to invite Thomas Heine to a News and Views article, which was published this week. Under the title "Making 2D Topological Polymers a reality" Prof. Heine describes how his theory became a reality.
Ultrathin materials are extremely interesting as building blocks for next generation nano electronic devices, as it is much easier to make circuits and other...
Scientists took a leukocyte as the blueprint and developed a microrobot that has the size, shape and moving capabilities of a white blood cell. Simulating a blood vessel in a laboratory setting, they succeeded in magnetically navigating the ball-shaped microroller through this dynamic and dense environment. The drug-delivery vehicle withstood the simulated blood flow, pushing the developments in targeted drug delivery a step further: inside the body, there is no better access route to all tissues and organs than the circulatory system. A robot that could actually travel through this finely woven web would revolutionize the minimally-invasive treatment of illnesses.
A team of scientists from the Max Planck Institute for Intelligent Systems (MPI-IS) in Stuttgart invented a tiny microrobot that resembles a white blood cell...
19.05.2020 | Event News
07.04.2020 | Event News
06.04.2020 | Event News
29.05.2020 | Materials Sciences
29.05.2020 | Materials Sciences
29.05.2020 | Power and Electrical Engineering