Researching the cures


Pulling the plug on calcium pumps – potential new treatment strategy for pancreatic cancer

A PCRF-funded project has identified a new way to kill pancreatic cancer cells by ‘pulling the plug’ on the energy generator that fuels calcium pumps on their cell surface.

Jason Bruce and co-researcher Andrew James in the labThe study, conducted at the University of Manchester, reports how switching off the cancer’s energy supply causes the pancreatic cancer cells to become ‘poisoned’ by an irreversible build-up of calcium.

Calcium inside cells is normally beneficial as it controls numerous cell functions. However, calcium levels are tightly controlled and normally kept at very low levels, as prolonged elevations in calcium lead to cell death. This tight control is achieved by calcium pumps on the cell surface that use chemical energy to pump calcium out of the cell. The researchers discovered that switching off the cancer cells’ energy supply causes these pumps to fail and calcium to rise, much like a damaged boat taking on water.

Lead researcher Dr Jason Bruce, from the University’s Division of Cancer Sciences said: “Identifying potential weaknesses of pancreatic cancer cells that could be exploited to selectively kill them – essentially finding their ’Achilles Heel’ – must remain a central research strategy if we are to tackle this devastating disease.”

The research identified that pancreatic cancer cells have a unique way of extracting energy from sugar to fuel their calcium pumps. They use a specific enzyme, called PKM2, which the researchers found in high levels in tumours compared to surrounding healthy tissue of patients with pancreatic cancer. They also found that the amount of PKM2 in tumours correlated with poor patient survival, suggesting this could be targeted to treat pancreatic cancer.

The team carried out experiments on pancreatic cancer cells in the laboratory to find out what would happen if they shut down PKM2. They used two different approaches. The first approach targeted the machinery responsible for making PKM2 protein, which eventually led to a dramatic reduction of PKM2 within the cancer cells. The second approach used a naturally occurring plant compound, called shikonin, which blocks PKM2 from working. Shikonin was originally extracted from the dried roots of the Arnebia plant, which has been used in traditional Chinese medicine.

Shikonin was very effective at killing pancreatic cancer cells within just a few hours of treatment. Treated cells had depleted energy levels, which in turn led to the failure of their calcium pumps and a toxic rise in calcium. Shikonin also prevented the cells from growing and migrating, which implies an impact on cancer spread.

However, although shikonin proved to be very effective in the laboratory tests, it may have additional unwanted side effect that would make it less useful in patients.

The team now aims to design new drugs that target this process to kill pancreatic cancer cells, while leaving healthy cells which rely on different energy sources unharmed.

The study is published in the British Journal of Cancer.