Biological Functions of Gasdermins in Cancer: From Molecular Mechanisms to Therapeutic Potential

Abstract

Pyroptosis is a type of lytic programmed cell death triggered by various inflammasomes that sense danger signals. Pyroptosis has recently attracted great attention owing to its contributory role in cancer. Pyroptosis plays an important role in cancer progression by inducing cancer cell death or eliciting anticancer immunity. The participation of gasdermins (GSDMs) in pyroptosis is a noteworthy recent discovery. GSDMs have emerged as a group of pore-forming proteins that serve important roles in innate immunity and are composed of GSDMA-E and Pejvakin (PJVK) in human. The N-terminal domains of GSDMs, expect PJVK, can form pores on the cell membrane and function as effector proteins of pyroptosis. Remarkably, it has been found that GSDMs are abnormally expressed in several forms of cancers. Moreover, GSDMs are involved in cancer cell growth, invasion, metastasis and chemoresistance. Additionally, increasing evidence has indicated an association between GSDMs and clinicopathological features in cancer patients. These findings suggest the feasibility of using GSDMs as prospective biomarkers for cancer diagnosis, therapeutic intervention and prognosis. Here, we review the progress in unveiling the characteristics and biological functions of GSDMs. We also focus on the implication and molecular mechanisms of GSDMs in cancer pathogenesis. Investigating the relationship between GSDMs and cancer biology could assist us to explore new therapeutic avenues for cancer prevention and treatment.

Pyroptosis-Related Gene Signature Predicts Prognosis and Indicates Immune Microenvironment Infiltration in Glioma

“…Mitochondrial dysfunction could trigger caspase-9 activation and subsequently cleaves and activates caspase-3. Active caspase-3 then cleaves GSDME to GSDME-NT, thus leading to pore-formation on the cell membrane, which is the hallmark for pyroptosis ( Wang et al, 2021b ). When GSDME is defective, cells are more prone to apoptosis.…”

“…Pyroptosis could promote anti-tumor inflammatory responses and tumor regression; however, on the contrary, other studies found that pyroptosis may also facilitate the supportive tumor microenvironment. ( Hergueta-Redondo et al, 2014 ; Gao et al, 2018 ; Wang et al, 2018 ; Tan et al, 2020 ; Wang et al, 2021a ; Loveless et al, 2021 ). Thus, the role of pyroptosis remains inconclusive and may differ in different tumors.…”

A Bibliometric Analysis of Pyroptosis From 2001 to 2021

“…Normally, moderate pyroptosis is conducive to the timely removal of infected cells. Nevertheless, excessive activation of pyroptosis leads to a large number of cell deaths and inflammatory cascade reactions, seriously damaging tissues and organs, and even leading to organ failure, which is closely related to the pathogenesis of certain diseases (75)(76)(77)(78)(79). A large number of studies have shown that pyroptosis is widely involved in the occurrence and progression of infectious diseases (80), metabolic diseases (81), tumors (82), nervous system diseases (83) and cardiovascular diseases (84).…”

Pyroptosis at the forefront of anticancer immunity

“…Given the dual role of pyroptosis, its molecular components are, as one would expect, abnormally and differentially expressed across different cancers (Table 2 ). GSDMs, for instance, are deregulated in breast, gastric, cervical, and lung cancers, among others, and have been shown to control proliferation, metastasis, therapeutic resistance, and antitumor immunity while acting as either oncogenes or tumor suppressors [ 65 , 66 ]. In gastric cancer (GC), GSDMD expression was markedly decreased and resulted in enhanced tumor proliferation both in vitro and in vivo, possibly by accelerating S/G2 cell transition [ 57 ].…”