Novel cell death mechanism may hold potential for novel cancer treatment strategies: Study

A study from researchers at The University of Texas MD Anderson Cancer Center, details a previously unexplained type of cell death called disulfidptosis that could open the door for novel cancer therapeutic strategies.

Many cancers, such as lung cancer and kidney cancer, have an overexpression of SLC7A11, which codes for the cystine transporter.The SLC7A11 protein imports cystine, an important amino acid that can contribute to tumor growth, but elevated levels of cystine and other disulfide molecules can be toxic. To regulate this balance, cells are forced to use the molecule NADPH to quickly convert toxic disulfides into other non-toxic molecules. NADPH is mainly supplied from glucose, so cutting off the glucose supply can lead to an accumulation of disulfide molecules and cell death.

One of the best-known cell death mechanisms is apoptosis, which can be triggered either internally or externally, resulting in the activation of caspases which kill the cell by chopping up key proteins. Another highly studied cell death pathway in recent years is ferroptosis, which is caused by the accumulation of lipid peroxides.

Disulfidptosis is different from these other cell death mechanisms because it relates to the actin cytoskeleton, a cell structure vital for maintaining cell shape and survival. The actin cytoskeleton is composed of actin filaments, which give cells their overall shape and structure.

This new study revealed that, in glucose-starved SLC7A11-high cancer cells, the large number of accumulated disulfide molecules cause aberrant disulfide bonding among actin cytoskeleton proteins, interfering with their organization and ultimately leading to actin network collapse and cell death. These findings suggest that targeting disulfidptosis merits further study as a cancer treatment approach.

Reference:

Boyi Gan et al,Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis, Nature Cell Biology,doi 10.1038/s41556-023-01091-2