Pancreatic cancer is an aggressive cancer with poor prognosis and limited treatment options and is highly resistant to chemotherapy and radiotherapy.
But researchers believe they have found an effective strategy for selectively killing pancreatic cancer while sparing healthy cells which could make treatment more effective.
Dr Jason Bruce, from the Physiological Systems and Disease Research Group, who led the research, said: “Pancreatic cancer is one of the most aggressive and deadly cancers. Most patients develop symptoms after the tumour has spread to other organs. To make things worse, pancreatic cancer is highly resistant to chemotherapy and radiotherapy. Clearly a radical new approach to treatment is urgently required. We wanted to understand how the switch in energy supply in cancer cells might help them survive.”
The research, published in The Journal of Biological Chemistry this month, found pancreatic cancer cells may have their own specialised energy supply that maintains calcium levels and keeps cancer cells alive.
Maintaining a low concentration of calcium within cells is vital to their survival and this is achieved by calcium pumps on the plasma membrane.
This calcium pump, known as PMCA, is fuelled using ATP – the key energy currency for many cellular processes.
All cells generate energy from nutrients using two major biochemical energy “factories”, mitochondria and glycolysis. Mitochondria generate approximately 90% of the cells’ energy in normal healthy cells. However, in pancreatic cancer cells there is a shift towards glycolysis as the major energy source. It is thought that the calcium pump may have its own supply of glycolytic ATP, and it is this fuel supply that gives cancer cells a survival advantage over normal cells.
Scientists used cells taken from human tumours and looked at the effect of blocking each of these two energy sources in turn.
Their study, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), National Institute of Health Research (NIHR) Biomedical Research Centre and AstraZeneca, shows that blocking mitochondrial metabolism had no effect. However, when they blocked glycolysis, they saw a reduced supply of ATP which inhibited the calcium pump, resulting in a toxic calcium overload and ultimately cell death.
Dr Bruce added: “It looks like glycolysis is the key process in providing ATP fuel for the calcium pump in pancreatic cancer cells. Although an important strategy for cell survival, it may also be their major weakness.
“Designing drugs to cut off this supply to the calcium pumps might be an effective strategy for selectively killing cancer cells while sparing normal cells within the pancreas.”
Maggie Blanks, CEO of the national charity, the Pancreatic Cancer Research Fund said: “These findings will certainly of great interest to the pancreatic cancer research community and we’d be keen to see how this approach progresses. Finding weaknesses that can be exploited in this highly aggressive cancer is paramount, so we want to congratulate the Manchester team for their discovery.”
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Glycolytic ATP Fuels the Plasma Membrane Calcium Pump Critical for Pancreatic Cancer Cell Survival
The Journal of Biological Chemistry, Vol. 288, Issue 50, 36007-36019, December 13, 2013
Andrew D. James; Oihane Erice; Jason I. E. Bruce
University of Manchester
This work was supported by a Biotechnology and Biological Sciences Research Council (BBSRC) New Investigator Grant (to Jason Bruce) and an National Institutes of Health Research (NIHR) Biomedical Research Centre (BRC) pump priming fund (to Ajith Siriwardena and Jason Bruce). Andrew James was supported by BBSRC and AstraZeneca CASE Ph.D. studentship.
Information about pancreatic cancer:
Has the worst survival rate of any common cancer – only 3 in every 100 people diagnosed will live beyond 5 years.
It is a highly aggressive cancer, but symptoms are vague and generally only appear in the later stages of the disease.
With no early diagnostic test, only 10% of patients are diagnosed early enough for surgery, currently the only potentially curative treatment.
Despite being the UK’s 5th biggest cancer killer, pancreatic cancer receives less than 2% of national research funding.
Some 8,500 people are diagnosed every year.
Manchester Cancer Research Centre
The Manchester Cancer Research Centre (MCRC) is a partnership founded by The University of Manchester, including the Paterson Institute for Cancer Research, The Christie NHS Foundation Trust and Cancer Research UK. The MCRC brings together the expertise, ambition and resources of its partner organisations in the fields of cancer treatment and clinical research and provides outstanding facilities where researchers and clinicians can work closely together. The aim of the MCRC is to improve understanding of how cancer develops, in order to translate basic and clinical research into new diagnostic tests and treatments that benefit cancer patients. More information is available at: www.manchester.ac.uk/mcrc
The Manchester Biomedical Research Centre is a partnership between Central Manchester University Hospitals NHS Foundation Trust and The University of Manchester, with the aim of improving health through science. www.manchesterbrc.org