Their discovery, reported in the latest edition of the New England Journal of Medicine, centres on the significance of DNA damage for both normal cells and cancer cells. It reveals that a biochemical signalling pathway, that normally ensures damaged cells are diverted towards cellular suicide, is blocked in certain cancers, rendering them resistant to certain types of treatment.
DNA damage is a common event in a cell’s life, a consequence of incorrect copying of the DNA during cell division or provoked by elements in our environment like tobacco smoke and sunlight. However, if DNA damage occurs, the cell normally triggers a repair response and if the damage is not repaired, the cell is targeted for cell death, a process known as apoptosis. In this way the body protects itself from cells that might become cancerous. The cells that do become cancerous manage to by-pass these repair and self-destruction pathways, promoting the survival of damaged cells.
The research is a collaboration between the BBSRC-funded Babraham Institute, the University of Cambridge and Addenbrooke’s Hospital, using cells from patients with chronic myeloid leukaemia (CML), and polycythemia vera (PV), two myeloproliferative disorders.
Cancers, such as the leukaemias investigated in this work, are characterised by an accumulation of DNA damage. DNA damage triggers several pathways to ensure that cells die by apoptosis. The authors describe a key new pathway involved in this process, and its subversion in cancer cells.
The team have found that DNA damage in normal cells increases the activity of a proton pump located in the cell membrane, known as NHE-1, which raises the pH of the cell. This has a critical effect on a protein called Bcl-xL, known as a survival protein because of its ability to suppress cell death. However, in the more alkaline environment (higher pH) a chemical process called deamidation converts Bcl-xL into a form that allows cells with damaged DNA to die. The authors have discovered that this pathway is inhibited in (cancerous) myeloid cells, keeping them alive to proceed with their deadly mission. This is the first demonstration of a role for deamidation in human malignancy.
Both the leukaemias studied by the authors are caused by oncogenic tyrosine kinases. These are enzymes - chemical catalysts - that trigger cancer when their activity is abnormally high. These kinases not only cause cells to become cancerous in the first place, but also make the cells resistant to chemotherapy and radiotherapy once they have turned into cancer cells. The authors have discovered that it is these kinases that block the key Bcl-xL deamidation pathway that normally allows DNA damaged cells to die. The activated tyrosine kinase causing CML is called BCR-ABL, whereas in PV the culprit is JAK-2. Altogether more than 30 aberrant tyrosine kinases are known to cause human cancers.
“This discovery provides new insights into how oncogenes, the genes that cause cancer, allow cells to accumulate more and more damage to their DNA without dying”, explains Dr Denis Alexander. “This new understanding of how oncogenes work also opens up some interesting ideas for future cancer therapies".
Cancer therapies depend to a large degree on the DNA damage caused by chemotherapy or radiotherapy, causing cancer cells to die. However, in cancers caused by tyrosine kinases the cells are often resistant to such therapies, referred to as ‘genotoxic resistance’. Fortunately inhibitors of the oncogenic kinases are now being increasingly used in the clinic but the kinases sometimes mutate so that this therapy no longer works.
The therapeutic interest in this research comes from the authors’ finding that simply switching back on the Bcl-xL deamidation pathway causes the cancer cells to die. This can be engineered in living cells by increasing the pH inside the cells artificially, which causes the Bcl-xL to deamidate so that the cells undergo apoptosis.
This therapeutic ‘proof-of-principle’ was dramatically illustrated by studying a CML patient’s cells which had become resistant to Imatinib, the BCR-ABL inhibitor now widely used in the clinic. As expected, Imatinib was unable to restore the Bcl-xL deamidation pathway in the patient’s cells. But the resistance could be bypassed by artificially (genetically) increasing the level of NHE-1 in the drug-resistant CML cells when studied in the laboratory, so increasing cancer cell death. So drug resistance can be overcome by activating the NHE-1 pathway, thereby increasing the pH inside the cell, and in turn Bcl-xL deamidation and apoptosis.
The discovery that modulating the NHE-1/Bcl-xL signalling pathway can override resistance to controlled cell death (apoptosis) in cancers like CML and PV, paves the way for new therapeutic approaches that could be of immense importance in cancers where Bcl-xL plays a pivotal role in genotoxic resistance.
This research was supported by the Association for International Cancer Research, the Biotechnology and Biological Sciences Research Council (BBSRC), the U.K. Leukaemia Research Fund, the Wellcome Trust, the U.K. Medical Research Council, Cancer Research UK, and the U.S. Leukemia and Lymphoma Society.
Dr Denis Alexander | alfa
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy