The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer

Abstract

Cancer is a category of diseases involving abnormal cell growth with the potential to invade other parts of the body. Chemotherapy is the most widely used first-line treatment for multiple forms of cancer. Chemotherapeutic agents act via targeting the cellular apoptotic pathway. However, cancer cells usually acquire chemoresistance, leading to poor outcomes in cancer patients. For that reason, it is imperative to discover other cell death pathways for improved cancer intervention. Pyroptosis is a new form of programmed cell death that commonly occurs upon pathogen invasion. Pyroptosis is marked by cell swelling and plasma membrane rupture, which results in the release of cytosolic contents into the extracellular space. Currently, pyroptosis is proposed to be an alternative mode of cell death in cancer treatment. Accumulating evidence shows that the key components of pyroptotic cell death pathways, including inflammasomes, gasdermins and pro-inflammatory cytokines, are involved in the initiation and progression of cancer. Interfering with pyroptotic cell death pathways may represent a promising therapeutic option for cancer management. In this review, we describe the current knowledge regarding the biological significance of pyroptotic cell death pathways in cancer pathogenesis and also discuss their potential therapeutic utility.

Natural Products as Inducers of Non-Canonical Cell Death: A Weapon against Cancer

“…Pyroptosis is closely linked to cancer, where it acts as a double-edged sword. Indeed, as an inflammatory cell death process, pyroptosis could promote tumor cell growth by different pro-tumorigenic mechanisms [ 168 , 169 ]; conversely, it could suppress tumors development [ 168 ] also by enhancing anti-tumor immunity [ 170 , 171 , 172 ].…”

DNA methylation downregulated ZDHHC1 suppresses tumor growth by altering cellular metabolism and inducing oxidative/ER stress-mediated apoptosis and pyroptosis

“…Morphologically, pyroptotic cells exhibit swelling and membrane rupture. It is believed that pyroptosis might play dual roles in terms of tumorigenesis 16 , inspiring us to hunt for new treatment targeting pyroptosis alteration. Nowadays, newly developed strategies have been focusing on involving pyroptosis to create a more efficacious way for inhibiting tumor formation and metastasis 17 - 19 .…”

A Small Molecule Stabilizer of the MYC G4-Quadruplex Induces Endoplasmic Reticulum Stress, Senescence and Pyroptosis in Multiple Myeloma

“…During MM pathogenesis, a network of stress mechanisms including endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) and are frequently activated by enhanced antibody production [ 28 , 57 , 58 ]. These pathways and others involved in cell death, inflammation and cell cycle regulation were altered in myeloma cells treated with D089 after 0.5, 1, 2, 4 and 8 h. MYC gene expression levels showed an initial increase followed by a marked decrease at later time points.…”

“…The activated pyroptotic inflammatory sensors NLRP3, AIM2 and pyrin recruit pro-caspase 1 with the help of apoptosis-associated speck-like protein containing a CARD domain (ASC) [ 23 ], an adaptor protein which consists of a pyrin domain (PYD) and a caspase recruitment domain (CARD). Pyroptosis is frequently mediated by the protease-inflammatory caspases (-1, -4 and -5 in humans and -11 in mice) leading to the activation of inflammation [ 24 , 25 ]; it is characterized by assembly of inflammasomes, formation of large structures called pyroptosomes and pore formation in the cell membrane [ 20 , 26 , 27 , 28 , 29 , 30 ]. Pyroptosomes are an aggregation of ASCs and pro-caspase-1, which allows processing of caspase-1 into two active forms (p10 and p20) leading to secretion of potent endogenous pyrogenic molecules: interleukin-1β (IL-1β) and IL-18 inflammatory cytokines as well as high mobility group box 1 proteins (HMGB1) [ 31 , 32 ].…”