Can you kill cancer cells by cutting off their electricity supply? That’s the implication of a new look at how cells swap electrons. It could herald devices that assemble inside tumours to switch off their electric current and starve them to death.
Frankie Rawson at the University of Nottingham, UK, and his colleagues have detected subtle changes in the bioelectric currents emanating from different types of cancer cells. These changes hint at what metabolic changes have happened in the cells to enable the rapid division that is characteristic of cancer.
All biological cells use electrons to power themselves. In the early 2000s, however, it was discovered that cells can also send electrons outside their membranes along biological “relays” made of proteins and other molecules. But we didn’t know the significance of this trans-plasma membrane electron transfer (tPMET). “I think we’re only just starting to realise the importance,” says Rawson.
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People have long suspected that there is a link between the way cancer cells change their metabolism to spread and grow and changes to the way the cells do this trans-plasma electron transfer.
Normal cells produce almost all of their energy in the mitochondria, their internal “power stations”. But mitochondria can’t power the aggressive demands of a rapidly dividing cancer cell, so cancer cells dial down their mitochondria, and ramp up a metabolic pathway known as glycolysis, which converts sugar into energy.
Reducing the output from the mitochondria creates a problem, because free electrons build up inside the cell, clogging up the glycolysis process. To keep from starving, the cancer cells eject those extra electrons using tPMET.
“tPMET is like a safety valve,” says Patries Herst at the University of Otago, New Zealand. Indeed, the more invasive and aggressive a cancer, the more heavily it relies on glycolysis and then tPMET to get rid of the electrons.
There are several different types of tPMET with different functions, however, which has made it hard to study how they are involved in tumour growth. “There have been a lot of good investigations,” says Lars Jeuken at the University of Leeds, UK, “but no one had ever figured out how to directly measure the electron current.”
Rawson’s team suspected that the strength of these electron currents could reveal when a cell had turned cancerous.
“If there is a lot of voltage going through a cell’s membrane,” says Herst, “then that means they are using this system a lot, which could have implications for the level of aggressiveness and invasiveness of the cancer.”
Rawson and his colleagues looked at the strength of the electrical current for three different lung cancer cell lines, and it showed clear differences, allowing them tell which cancer cells were metastatic, or capable of spreading, and which were still non-invasive.
As the team suspected, when they engineered the cells to reduce the number of tPMET relays, their mitochondria were no longer able to produce enough energy and became overtaxed. But a surprise was in store: instead of the expected slowdown in electron transmission, they saw a “marked increase” in current, Rawson says, as the cells used any remaining tPMETs to fling out as many electrons as possible.
“This was a major, major finding for us,” says Rawson. “Because if you can inhibit that external electron transfer, the cells have limited ways to sustain energy, so they’ll either be unable to proliferate, or they’ll die.”
It also raises another possibility: if we could inhibit the electron transfer, we could starve cancer cells. No drugs are available that can interfere with tPMET, but the new research suggests that we could do it another way.
Paola Sanjuan-Alberte, also at the University of Nottingham, and Rawson have been working on self-assembling nano-electrodes that could interface with cancerous cells to tweak their electrical signalling. These devices apply an electrical field to prevent a cell’s relays from shedding the electrons.
However, Herst and Jeuken both caution that more studies need to be done to gain a deeper understanding of the role this electron transfer plays in normal and in healthy cells.
Biochimica et Biophysica Acta (BBA) - Bioenergetics
