The role of pyroptosis in cancer: pro-cancer or pro-"host"?

Abstract

Programmed cell death (PCD) refers to the way in which cells die depending on specific genes encoding signals or activities. Apoptosis, autophagy, and pyroptosis are all mechanisms of PCD. Among these mechanisms, pyroptosis is mediated by the gasdermin family, accompanied by inflammatory and immune responses. The relationship between pyroptosis and cancer is complex, and the effects of pyroptosis on cancer vary in different tissues and genetic backgrounds. On one hand, pyroptosis can inhibit the occurrence and development of tumors; on the other hand, as a type of proinflammatory death, pyroptosis can form a suitable microenvironment for tumor cell growth and thus promote tumor growth. In addition, the induction of tumor pyroptosis is also considered a potential cancer treatment strategy. Studies have shown that DFNA5 (nonsyndromic hearing impairment protein 5)/GSDME (Gasdermin-E) mRNA methylation results in lower expression levels of DFNA5/GSDME in most tumor cells than in normal cells, making it difficult to activate the pyroptosis in most tumor cells. During the treatment of malignant tumors, appropriate chemotherapeutic drugs can be selected according to the expression levels of DFNA5/GSDME, which can be upregulated in tumor cells, thereby increasing the sensitivity to chemotherapeutic drugs and reducing drug resistance. Therefore, induced pyroptosis may play a predominant role in the treatment of cancer. Here, we review the latest research on the anti- and protumor effects of pyroptosis and its potential applications in cancer treatment.

Fig. 1

Timeline summary of the history of pyroptosis

Fig. 2. Schematic representation of pyroptosis pathways.

The canonical pathway upon sensing DAMPs, PAMPs or other cytosolic disturbances results in the recruitment and activation of caspase-1 either directly or through recruitment of the receptor protein ASC. Caspase-1 successively promotes maturation of the precursors of IL-1β and IL-18 into mature forms and cleaves GSDMD. The pore form domain (PFD) of GSDMD interacts with the plasma membrane to form GSDMD pores, resulting in the release of intracellular contents, including IL-1β and IL-18. The noncanonical pathway is initiated by the caspase-11 self-detection of cytosolic LPS in Gram-negative bacteria. Activated caspase-11 (caspase-4 or caspase-5 in humans) successively cleaves GSDMD and induces pyroptosis. The other pathway of pyroptosis can be engaged through mechanisms such as CASP8-GSDMD and CASP3-GSDME. In turn, activated caspase-3 cleaves GSDME to produce GSDMD-cNT, which forms pores in the plasma membrane and activates pyroptosis. The bacteria are recognized by TLR4, which signals via RIP1 to form a cell death complex consisting of RIP1, caspase-8, and FADD. Both this complex cleavage of GSDMD and activation through caspase 1/11 and GSDME cleavage via caspase-3 lead to cell membrane permeabilization and subsequent pyroptosis. In addition, neutrophil elastase (NE) is able to cleave GSDMD independently of caspase activity

Fig. 3. Therapeutic targets of pyroptosis core proteins in cancer.

Drugs (chemotherapy drugs, new material, traditional Chinese medicines, etc.), miRNAs, receptor proteins, secreted factors of human umbilical cord mesenchymal stem cells, etc. can all modulate pyroptosis target core proteins in canonical, noncanonical, and other pathways for therapeutic benefit