Cell death discovery adds fresh angle to attack cancer

Cell death comes in many forms, depending on the trigger. During human embryonic development, for example, cells that make up the webbing between the fingers will undergo an orderly self-destruction known as apoptosis, enabling separation of the digits. Other cells have unplanned deaths, triggered by injury or toxins that sabotage cellular machinery. Programmed or not, cell death is an essential process that cancer is adept at avoiding.

“Most therapies are designed to kill tumour cells through apoptosis,” says Boyi Gan, who studies the life and death of cells at The University of Texas MD Anderson Cancer Center. “But tumour cells can often escape apoptosis, leading to disease persistence and recurrence.”

Gan’s lab investigates how other cell death mechanisms might be exploited in the fight against cancer.

With the exception of mechanical injury — where a cell is physically torn apart — cell death is carried out by a cascading network of enzymes. Malignant cells may evade death processes by downregulating key enzymes or suppressing the death-inducing trigger. However, when tumour cells become resistant to one form of death, they often become vulnerable to others.

In a paper published in Nature Cell Biology¹, Gan and colleagues detailed a new form of cellular sabotage called disulfidptosis, in which cells are overwhelmed by disulfide-containing compounds. While it’s unclear whether normal cells encounter this form of death naturally, some tumour cells appear to have adapted a survival mechanism that leaves them susceptible to disulfidptosis.

Disulfidptosis: a new form of cell death

A healthy cell generates reactive metabolites that can attach to and deteriorate its plasma membrane, a phenomenon called lipid peroxidation. To prevent this, cells import the amino acid cystine, which helps in the formation of glutathione, a potent antioxidant that can counteract lipid peroxidation. Without enough cystine, lipid peroxidation can trigger a form of cell death known as ferroptosis². Many tumour cells evade ferroptosis by overexpressing the cystine transport protein SLC7A11.

“When tumour cells have high levels of this transporter,” Gan explains, “it protects them from ferroptosis, but we found it also presents a vulnerability.”

Cystine contains reactive disulfide bonds that can react with various proteins throughout the cell, with toxic effect. Cells use the reducing agent NADPH to neutralize cystine, and NAPDH is mainly supplied from glucose. As such, cells that overexpress SLC7A11 become addicted to glucose — starving them of this energy source can lead to toxic buildup of cystine and trigger disulfidptosis.

Gan’s team found the buildup of cystine caused an accumulation of disulfide bonds in the actin cytoskeleton, and ultimately cell death. Inhibitors of apoptosis, ferroptosis and other cell death mechanisms had no effect on this process, suggesting disulfidptosis is a distinct pathway.

The discovery of disulfidptosis offers a new route to sabotage tumour cells that have grown resistant to ferroptosis while minimizing collateral toxicity. The researchers observed in preclinical models that cells overexpressing SLC7A11 quickly died of disulfidptosis when glucose uptake was inhibited. “This suggests a therapeutic potential of triggering this cell death in certain cancers,” says Gan.

There is still much to be learned about the mechanisms of disulfidptosis. Because SLC7A11 is known to be overexpressed in a range of tumour types³, if this work can be clinically validated, sabotage via this newly discovered cell death pathway could become a valuable addition to many oncologists’ toolbox.