Death by metal: a hidden detonator inside cancer cells?

Our cells are wired to explode. Given the right signals they can burst open, scattering bits of crunched up DNA, shrivelled membrane and chemicals in all directions. Sometimes this is all part of the plan: controlled cell death it vital to defining the outline of our toes and fingers in the womb, and to the daily act of replacing old cells with new ones. Cell death is a part of life.

Could pools of iron inside cancer cells be exploited
to trigger their demise?
Iron in Lake Khövsgöl, Mongolia
(picture credit Josefontheroad) 

New research has uncovered a hidden route to cell death. Death by iron, or 'ferroptosis' may be a secret weapon against some forms of cancer.

In work published recently in Cell, Scott Dixon and colleagues triggered the death  of cells in a dish using chemicals which causes a build-up of Reactive Oxygen Species (ROS). ROS are volatile and highly damaging to cells, so death within a few hours came as no surprise. What did was another observation: erastin was only effective in cells with a healthy supply of iron.

Iron absorbed from the blood stream (but not other heavy metals such as copper, nickel or cobalt) appeared to sensitise certain cells to erastin and a quick death. 

Exactly what the link is between ROS-inducing chemicals such as erastin and iron has yet to be uncovered. But the team from Columbia University, New York, found evidence that ferroptosis has a "unique genetic network" that is entirely separate from other forms of cell death such as apoptosis (the 'culling' of cells, apoptosis helped to create the gaps between our toes) and necrosis (triggered when a cell is too injured to repair).


This distinct wiring presents an intriguing opportunity: to selectively activate ferroptosis to kill certain cancer cells.

Can death by iron, or 'ferroptosis' be aimed at cancer?
Or blocked in nerve cells to protect the nervous system?
(Iron Maiden. ' The Trooper' (1983))

"The RAS family [of genes] is mutated in 30% of cancers," Dr Dixon writes. These mutations lead to uncontrolled cell division, but also "for better or worse... elevated levels of iron... are observed in some cancer cells".

His team believes it is possible to activate ferroptosis in RAS-mutated cancers inside the human body, using the abnormal iron levels to sensitise the cells to chemicals like erastin.

But activating ferroptosis in cancer may not be its only health benefit. There may be a use for blocking the process too.

The team successfully rescued neurons in rodent brains from cell death by blocking ferroptosis with a chemical inhibitor called ferrostatin-1. They propose that blocking ferroptosis in human brain cells following a stroke or epileptic fit (when ROS and iron levels are high) might protect the central nervous system from long-term damage.

Although the wiring inside our cells is complex (and multitasking is common), ferroptosis is a rare example of independence. Its distinct wiring may allow selective activation or inhibition of cell death, and maybe even the treatment of cancer with fewer side effects. That this metal-based killer might be used to protect life is, in more ways than one, quite ironic.

What does this mean for me?

This study might lead to a whole new line of approach for the treatment of some cancers and diseases which damage the central nervous system. High levels of iron have been reported in cases of Alzheimer's and Parkinson's disease. Understanding exactly how our cells are wired to use ferroptosis will make it easier for scientists to manipulate its effects with drugs similar to erastin or ferrostatin-1.

What does this mean for science?

The discovery of a previously unknown route to cell death shows just how much about our cells we have yet to understand. Indeed, the authors of this work suggest there may be much more "hidden" wiring  used by the cell, waiting to be discovered.

Reference:

Dixon, S., Lemberg, K., Lamprecht, M., Skouta, R., Zaitsev, E., Gleason, C., Patel, D., Bauer, A., Cantley, A., Yang, W., Morrison, B., & Stockwell, B. (2012). Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death Cell, 149 (5), 1060-1072 DOI: 10.1016/j.cell.2012.03.042