A study published in “Nature Cell Biology” reveals a new type of cell death, called dysulfiptosis, which opens a new avenue for cancer treatment.
As explained by researchers at the MD Anderson Cancer Center of the University of Texas (USA), this unknown cell death is triggered when cells with high levels of the SLC7A11 protein are subjected to sugar deprivation. In preclinical models, glucose inhibitor treatment killed cancer cells with high expression of this protein by inducing dysulfiptosis, effectively suppressing tumor growth without toxicity.
Many cancers, such as lung cancer and kidney cancer, have an overexpression of SLC7A11. Already in 2020, the team of Boyi Gan showed that certain cancer cells might be amenable to treatment with inhibitors.
The SLC7A11 protein imports cystine, an important amino acid that can contribute to tumor growth, but elevated levels of cystine and other molecules can be toxic.
To regulate this balance, cells are forced to use the NADPH molecule to quickly convert toxic disulfides into other, non-toxic molecules. NADPH is supplied primarily from glucose, so cutting off the glucose supply can lead to a buildup of disulfide molecules and cell death.
One of the best-known cell death mechanisms is apoptosis, which can be triggered internally or externally, resulting in the activation of caspases that kill the cell by cutting key proteins. Another cell death pathway that has been widely studied in recent years is ferroptosis, which is caused by the accumulation of lipid peroxides.
Many cancer therapies are designed to kill cancer cells through apoptosis.
Disulfidptosis is different from these other mechanisms of cell death because it involves the actin cytoskeleton, a vital cellular structure for maintaining cell shape and survival. The actin cytoskeleton is made up of actin filaments, which give cells their overall shape and structure.
This new study reveals that in glucose-starved SLC7A11-high cancer cells, the large number of accumulated disulfide molecules cause aberrant disulfide bonds between actin cytoskeletal proteins, interfering with their organization and ultimately , leads to the collapse of the actin network and cell death.
Many cancer therapies are designed to kill cancer cells through apoptosis. However, many cancer cells find ways to escape therapy-induced apoptosis, leading to therapy resistance and disease relapse.
These findings suggest that targeting dysulfidptosis needs further study as a cancer treatment approach..
“Hopefully, this important finding will inspire dysulfiptosis-inducing treatments for cancers that have evaded other therapies and are resistant to apoptosis,” says Gan. “Because SLC7A11 is highly expressed in many types of cancer, there might be a therapeutic window to inhibit glucose transporters and induce dysulfiptosis in these cells without affecting normal cells.”