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Pyroptosis - a new paradigm for cell death to fight cancer

Dr. Reshma Tendulkar & Rashmi Wani
Wednesday, September 14, 2022, 08:00 Hrs  [IST]

Pyroptosis is one of the kinds of programmed cell death (PCD) whose occurrence depends on the gasdermin protein family by producing inflammatory responses; causing cell death usually caused by microbial infection. This is accompanied by activation of inflammasomes and maturation of pro-inflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). Gasdermin family proteins are the executors of pyroptosis. A great deal of evidence shows that pyroptosis can affect the development of tumours. The relationship between pyroptosis and tumours is diverse in different tissues and genetic backgrounds.

Over the last few decades, according to researchers, evidence shows that pyroptosis has been found to be more closely related to the occurrence and development of tumours. Currently, worldwide tumours are mushrooming and an infinite number of people die every year due to tumours. In recent years, most studies show a close relationship between pyroptosis and tumour. The goal of cancer therapeutics, radiotherapy, chemotherapy and immunotherapy have done a great job in achieving the destruction of cancerous cells.

There are two categories of cell deaths like accidental cell death (ACD) and programmed cell death. ACD is referred to a biologically uncontrolled cell death or non-programmed cell death which usually presents as lytic or necrotic like form; it has been considered as a non-programmed cell death for a long time. Pyroptosis serves as a potential tumour treatment strategy and describes the side effects of radiotherapy and chemotherapy caused by pyroptosis.

Pyroptosis is closely related to nervous system diseases, infectious diseases, autoimmune diseases, cardiovascular diseases, and tumours. With further research, the relationship between pyroptosis and tumours is becoming increasingly clear, which provides some strategies for clinical treatments.

Characteristics of pyroptosis
In 2001, D’Souza et al. pointed out the term of pyroptosis, which comes from the Greek roots pyro meaning fire/fever and ptosis meaning falling, to describe pro-inflammatory programmed cell death. This is the first definition of pyroptosis, which makes the distinction between pyroptosis and apoptosis (a non- inflammatory program of cell death). Pyroptosis was considered to be caspase-1-induced monocyte death for a long time. Later, it was reported that caspase-1 or caspase-11/4/5 was activated during this process, and gasdermin D (GSDMD) was cleaved, and the N-terminal domain can oligomerize to form pores in the cell membrane, inducing cell membrane rupture.

There are some similarities between pyroptosis and apoptosis, such as DNA damage and chromatin condensation. Interestingly, pyroptotic cells emerged swelling and a lot of bubble-like protrusions appeared on the surface of the cellular membrane before its rupture. Similarly, membrane blebbing also occurs during apoptosis, and caspase-3 is necessary for this process.  

However, the unique morphological characteristics of pyroptosis are obviously different from those of apoptosis. It is generally believed that apoptosis is a safe form of death, but pyroptosis can cause inflammation, activated by extracellular or intracellular stimulation, such as bacterial, viral, toxin, and chemotherapy drugs. In fact, unlike the explosive rupture associated with necrosis, pyroptosis causes flattening of the cytoplasm due to plasma membrane leakage.  In addition, caspases activation or release of granzymes results in the N-terminal of gasdermin oligomerization and pore formation (1–2 µm in diameter) in the plasma membrane, which allows mature IL-1ß/IL-18 with a diameter of 4.5 nm and caspase-1 with a diameter of 7.5 nm to pass through, respectively. In the meantime, the water entering through the pores causes cell swelling and osmotic lysis, thus resulting in rupture of the plasma membrane and the release of IL-1ß and IL-18. Thus, the pyroptotic cells are permeable to 7-aminoactinomycin (7-AAD), Propidium Iodide (PI), and Ethidium Bromide (EtBr) because of the low molecular weight of these dyes. On the contrary, in comparison with pyroptotic cells, apoptotic cells maintain membrane integrity, so that these dyes can’t stain them. Intriguingly, similar to apoptotic cells, Annexin V also stains pyroptotic cells and the dye binds to phosphatidylserine (PS). Therefore, Annexin V cannot differentiate apoptotic cells from pyroptotic cells. In addition, apoptotic bodies are formed in the process of apoptosis, while pyroptotic bodies are formed in the process of pyroptosis.80 Interestingly, the diameter of pyroptotic bodies is similar to that of apoptotic bodies, and their size are both 1–5 µm.

Canonical pathway
Canonical pyroptotic death is mediated by inflammasome assembly, which is accompanied IL-1ß and IL-18 release. Inflammasomes are multimolecular complexes that are activated when the host is resistant to microbial infection and also facilitate the development of adaptive immune responses. In addition, Inflammasomes are also associated with non-microbial diseases. There is considerable evidence that inflammasomes and their related cytokines play crucial roles in oncogenesis, such as proliferation, metastasis, and invasion. The assembly of inflammasomes begins with cytosolic pattern recognition receptors (PRRs, also known as inflammasome sensors), which are capable of recognizing pathogen-associated molecular patterns and danger-associated molecular patterns ((PAMPs and DAMPs). Activation of PRRs promotes downstream signaling pathways and causes type I interferons generation and pro-inflammatory cytokines release.  PRRs assemble with pro-caspase-1 to form inflammasomes after stimulation of cells by signal molecules such as bacteria and viruses.

Role of pyroptosis in tumours
Pyroptosis may act as a pivotal part in multiple tumours. With further research, the relationship between pyroptosis and tumours has become increasingly understood and provides some inspiration for clinical treatments.

Pyroptosis and melanoma
Melanoma is a common malignant tumor and is typically associated with BRAF and NRAS mutations.  Previous work by Corey et al. found that the pyroptosis-related protein GSDME from B16-Ova cell lines exerted a tumor suppressive effect. In addition, it has been found that melanoma cells with GSDME deficiency generate larger tumors than wild-type melanoma cells; thus, GSDME may have real tumor inhibitory activity. In 2020, the combination of BRAF and MEK inhibitors was reported to induce GSDME-dependent pyroptosis in melanoma cells. In immunocompetent mice, BRAF inhibitor + MEK inhibitor caused an increase in CD4+ T cell and CD8+ T cell infiltration and a decrease in myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). In BRAF inhibitor + MEK inhibitor resistant tumors, the loss of pyroptosis and GSDME cleavage induced by BRAF inhibitor + MEK inhibitor was associated with a decreased antitumor immune response.

Pyroptosis and breast cancer
Breast cancer is one of the most frequent malignancies. A high level of Gas dermin B (GSDMB) in breast cancers was related to tumor progression, and over expression of GSDMB indicated a poor response to targeted treatment of HER-2. This means that GSDMB could be a novel prognostic marker for tumors.

Pyroptosis and colorectal cancer
Colorectal cancer is a heterogeneous disease associated with genetic mutations, age, family history, ethnicity, and lifestyle. The downregulation of Gas dermin C (GSDMC) led to significant decreases in the proliferation and of colorectal cancer cells, while GSDMC overexpression promoted cell proliferation, tumorigenesis suggesting that GSDMC may be a promising therapeutic target in colorectal cancer.

Pyroptosis and lung cancer
Lung cancer is one of the primary causes of death and the most common cancer in the world. GSDMD was found to be upregulated in non-small cell lung cancer (NSCLC).

Pyroptosis and cervical cancer
Cervical cancer is one of the most common female malignant tumors worldwide and is one of the primary causes of tumor death among women. The researchers found that HeLa cells with GSDMB overexpression showed obvious characteristics of pyroptosis. In addition, the release of GzmB by immune cells cleaved GSDME and promoted HeLa cell pyroptosis, which is an important finding for understanding the interaction between GSDME-mediated cell death and the immune system.

Conclusion
As an inflammatory and programmed mode of cell death, pyroptosis has been gradually elucidated with further research, but there are still some problems to be solved, such as what other factors regulate pyroptosis and what role other members of the gasdermin family play in pyroptosis.  Different forms of pyroptosis are closely related to tumors. Currently, researchers have been trying to improve the therapeutic efficacy through pyroptosis or combining pyroptosis with a variety of tumour treatment methods.

(Authors are with Vivekanand Education Society’s College of Pharmacy, Mumbai 400 074)

 

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