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Targeting Pyroptosis – A Promising Strategy for Overcoming Chemotherapy Resistance?

A new study published in Science suggests that targeting pyroptosis, a type of programmed cell death, may be a promising strategy for overcoming resistance to chemotherapy treatments in pancreatic and lung cancer. The study found that a protein called β5-integrin, high levels of which are associated with poor patient outcomes and lack of response to chemotherapy, represses pyroptosis conferring chemoresistance. By inhibiting the protein Src or the enzyme ceramidase, researchers were able to reactivate pyroptosis and improve cancer cells’ response to chemotherapy treatment in vitro and in vivo.

Understanding pyroptosis

Chemotherapy is a treatment used for multiple different cancers and works by inducing apoptotic cell death. However, cancer cells often develop chemoresistance. To overcome this resistance, researchers in this study turned to a different type of cell death called pyroptosis. Pyroptosis is a gasdermin-dependent programmed necrotic death – gasdermins are a family of pore-forming proteins that have only very recently been implicated in pyroptosis and the immune response.

Pyroptosis plays an important regulatory role in pathological diseases and cancers, but the relationship between pyroptosis and cancer chemoresistance is not well understood. Previous studies have suggested that the caspase-3/GSDME (gasdermin E) pathway, which connects apoptosis and pyroptosis, modulates a switch between chemotherapy-induced apoptosis and pyroptosis in certain cell lines.However, GSDME expression is silenced in most cancers.

Another pathway, the caspase-1/GSDMD (gasdermin D) pathway, is a more attractive target for pyroptosis-based therapy, as unlike GSDME, GSDMD is widely expressed in cancers. That being said, it is still uncertain whether chemotherapy can induce pyroptosis in pancreatic and lung cancer cells.

Recently, previous studies by the same team and others have also shown that the protein β5-integrin plays a role in cancer cell survival and chemosensitivity, but its functional role in pyroptosis is unknown. Integrins are transmembrane receptors. They facilitate cell adhesion to the extracellular matrix to activate intracellular signalling pathways. A growing body of evidence suggests that sphingolipid metabolism may be involved in chemotherapy-induced pyroptosis. Sphingolipids are important for the maintenance of cell membrane integrity and intracellular signalling activity, and ceramide is the main intermediate of sphingolipid metabolism, as well as being a signalling molecule involved in many cellular processes – including cell death. Previous studies have shown that chemotherapy treatment can activate sphingomyelinase (SMase), leading to sphingomyelin (SM) hydrolysis, producing ceramide in cancer cells. This increased ceramide concentration has been linked to cancer chemosensitivity.

Unexpected results

In this study, researchers used cancer cell lines, patient-derived tumor organoids, and orthotopic lung and pancreatic animal models to investigate how β5-integrin, ceramide, and GSDMD confers chemoresistance by repressing pyroptosis in cancer cells. The data shows that cancer cells increase expression of the protein β5-integrin by activating the Src-STAT3-ASAH2 pathway and reducing the production of reactive oxygen species (ROS) through regulation of ceramide levels. Furthermore, they showed that pancreatic and lung cancer cell lines express GSDMD, but not other members of the gasdermin family, and that chemotherapeutic agents can induce pyroptosis in wild-type cancer cells but not in chemoresistant cells, which are controlled by β5-integrin.

As the authors of this study note, “These results are not expected and call for reconsideration for the role of pyroptosis in direct control of cancer chemoresistance and progression.” However, this study does have its limitations, as it does not explore the effect of chemotherapy-induce pyroptosis in human cancer patient samples, and cancer studies are notorious for having a low animal to clinic translation rate (less than 8% according to some studies). However, if these results do translate, targeting pyroptosis could a potentially effective adjuvant therapy boosting the efficacy of chemotherapy.