Cell death takes many forms, depending on the trigger. For example, during human embryonic development, the cells that form the web between the fingers undergo an orderly self-destruction known as apoptosis that allows the fingers to separate.
Other cells have unscheduled death caused by injury or toxins that sabotage the cellular machinery. Cell death, whether programmed or not, is a fundamental process that cancer can avoid.
“Most therapies are designed to kill tumor cells through apoptosis,” says Boyi Gan, who studies cell life and death at the University of Texas MD Anderson Cancer Center. “But tumor cells can often escape apoptosis, leading to disease persistence and recurrence.”
Gan’s lab is investigating how other mechanisms of cell death can be used to fight cancer. With the exception of mechanical damage when the cell is physically torn cell death is carried out by a cascading network of enzymes. Malignant cells can evade death processes by downregulating key enzymes or suppressing a death-inducing trigger. However, when tumor cells become resistant to one form of death, they often become vulnerable to others.
In a paper published in Nature Cell Biology, Gan and his colleagues detailed a new form of cellular sabotage called disulfide ptosis, in which cells are overwhelmed with disulfide-containing compounds.
Although it is unclear whether normal cells encounter this form of death naturally, some tumor cells appear to have adapted a survival mechanism that makes them susceptible to disulfide ptosis.
Disulfideptosis: a new form of cell death
A healthy cell produces reactive metabolites that can attach to its plasma membrane and damage it, a phenomenon called lipid peroxidation. To prevent this, cells import the amino acid cystine, which helps produce glutathione, a powerful antioxidant that can counteract lipid peroxidation. Without sufficient cystine, lipid peroxidation can trigger a form of cell death known as ferroptosis. Many tumor cells evade ferroptosis by overexpressing the cystine transport protein SLC7A11.
“When tumor cells have high levels of this transporter,” explains Gan, “it protects them from ferroptosis, but we found that it also presents a vulnerability.”
Cystine contains reactive disulfide bonds that can react with various proteins throughout the cell with a 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 dependent on glucose starving these energy sources can lead to a toxic build-up of cystine and trigger disulfide ptosis.
Gan’s team found that the accumulation of cystine caused the 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 that disulfideptosis is a distinct pathway.
The discovery of disulfideptosis offers a new way to sabotage tumor cells that have grown resistant to ferroptosis while minimizing collateral toxicity. The researchers observed in preclinical models that cells overexpressing SLC7A11 rapidly died from disulfide ptosis when glucose uptake was inhibited. “This suggests the therapeutic potential of triggering this cell death in certain cancers,” says Gan.
Much remains to be learned about the mechanisms of disulfide ptosis. Since SLC7A11 is known to be overexpressed in a number of tumor types,3 if this work can be clinically validated, sabotage through this newly discovered cell death pathway could become a valuable addition to many oncologists’ toolkits.
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Reference: https://www.nature.com/articles/d42473-023-00033-8
