Role of Pyroptosis in Endometrial Cancer and Its Therapeutic Regulation

Abstract

Pyroptosis is an inflammatory cell death induced by inflammasomes that release several pro-inflammatory mediators such as interleukin-18 (IL-18) and interleukin-1β (IL-1β). Pyroptosis, a type of programmed cell death, has recently received increased interest both as a therapeutic and immunological mechanism. Numerous studies have provided substantial evidence supporting the involvement of inflammasomes and pyroptosis in a variety of pathological conditions including cancers, nerve damage, inflammatory diseases and metabolic conditions. Researchers have demonstrated that dysregulation of pyroptosis and inflammasomes contribute to the progression of endometriosis and gynecological malignancies. Current research also indicates that inflammasome and pyroptosis-dependent signaling pathways may further induce the progression of endometrial cancer (EC). More specifically, dysregulation of NLR family pyrin domain 3 (NLRP3) and caspase-1-dependent pyroptosis play a contributory role in the pathogenesis and development of EC. Therefore, pyroptosis-regulated protein gasdermin D (GSDMD) may be an independent prognostic biomarker for the detection of EC. This review presents the molecular mechanisms of pyroptosis-dependent signaling pathways and their contributory role and function in advancing EC. Moreover, this review offers new insights into potential future applications and innovative approaches in utilizing pyroptosis to develop effective anti-cancer therapies.

Keywords: GSDMD; IL-18; IL-1β; NLRP3; caspase-1; endometrial cancer; pyroptosis.

Graphical abstract

Figure 1

Cellular and molecular mechanisms of pyroptosis-dependent signaling pathways. Pyroptotic signaling pathways are mainly triggered by the stimulation of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), leading to the activation of a variety of inflammasome components. The activated inflammasome proteins further activate the caspase-1 pathway. Then, the activated caspase-1 splits GSDMD to produce GSDMD N-fragment and plasma membrane pores, resulting in pyroptosis-dependent cell death. Furthermore, the caspase-1 pathway triggers the formation and release of IL-1β and IL-18 inflammatory factors. In addition, LPS binds to caspase-4/5/11 precursor, inducing pyroptosis. Caspase-3/GSDME can also cause pyroptosis-mediated cell death. Mitochondrial and death receptors can also trigger the caspase-3 pathway. The activated caspase-3 splits GSDME to produce GSDME N-fragment, creating plasma membrane pores, cell contraction and rupture and resulting in pyroptosis-mediated cell death.

Figure 2

The pathophysiological mechanisms of pyroptosis-related signaling pathways in the progression of EC.

Figure 3

The schematic strategy for the pharmacological induction of pyroptosis-mediated cancer cell death for the therapeutic regulation of EC.