Pyroptosis: shedding light on the mechanisms and links with cancers

Abstract

Pyroptosis, a novel form of programmed cell death (PCD) discovered after apoptosis and necrosis, is characterized by cell swelling, cytomembrane perforation and lysis, chromatin DNA fragmentation, and the release of intracellular proinflammatory contents, such as Interleukin (IL) 8, IL-1β, ATP, IL-1α, and high mobility group box 1 (HMGB1). Our understanding of pyroptosis has increased over time with an increase in research on the subject: gasdermin-mediated lytic PCD usually, but not always, requires cleavage by caspases. Moreover, new evidence suggests that pyroptosis induction in tumor cells results in a strong inflammatory response and significant cancer regression, which has stimulated great interest among scientists for its potential application in clinical cancer therapy. It's worth noting that the side effects of chemotherapy and radiotherapy can be triggered by pyroptosis. Thus, the intelligent use of pyroptosis, the double-edged sword for tumors, will enable us to understand the genesis and development of cancers and provide potential methods to develop novel anticancer drugs based on pyroptosis. Hence, in this review, we systematically summarize the molecular mechanisms of pyroptosis and provide the latest available evidence supporting the antitumor properties of pyroptosis, and provide a summary of the various antitumor medicines targeting pyroptosis signaling pathways.

Keywords: cancers; caspase; cell death; gasdermin; pyroptosis.

Figure 1

Sketch of essential components and primary mechanisms of pyroptosis. In the canonical inflammasome pathway, PRRs recognize DAMP and/or PAMP, leading to the assembling and activation of inflammasomes and subsequently contributing to the recruitment and activation of pro-caspase-1. GSDMD and pro-IL-18/1β will be cleaved to N-GSDMD and inflammatory IL-18/1β by acitivated cleaved-caspase-1. N-GSDMD punches noneselective pores on cell membrane, resulting in water influx, cell swelling, inflammatory factors release, and cell death. In the non-canonical pathway, Gram-negative bacteria-derived LPS cleaves and activates caspase-4/5/11, inducing pyroptosis via cleaving GSDMD. Chemotherapy drugs can trigger pyroptosis through stimulating caspase-3 and GSDME cleavage. N-GSDME possesses the similar cell membrane perforation function to N-GSDMD, which leads to cellular perfusion, increased intracellular osmotic pressure and various inflammatory mediator outflow. In addition, CTLs- and NK cells-released GZMA can cleave GSDMB to N-GSDMB, contributing to the GSDMB pore formation on cell membrane and induce pyroptosis. CAR-T cells-derived GZMB can cleave GSDME to N-GSDME and induce pyroptosis. What’s more, TAK1 inhibition and TNF-α are able to activate caspase-8, which will further cleave GSDMC to N-GSDMC and induce pyroptosis. Under hypoxia, the transcription and cleavage of GSDMC specifically mediated by caspase-8 is enhanced via p-STAT3 physically interaction with PD-L1.

Figure 2

Various human cancers associated with pyroptosis. The complex function of pyroptosis is widely involved in different human cancers, including but not limited to the reproductive system cancers, such as breast cancer, ovarian cancer, cervical cancer etc. the digestive system cancers, such as gastric cancer, liver cancer, colorectal cancer, oral squamous cell carcinoma, esophageal squamous cell carcinoma etc. the respiratory system cancer, such as lung cancer, nasopharynged carcinoma etc. the nervous system cancer, such as brain tumors and malignant mesothelioma etc.