Inflammasomes in cancer: Effect of epigenetic and autophagic modulations
Introduction
Inflammation plays a crucial role in cancer and is involved in tumour initiation, malignant transformation, invasion and metastasis [1], [2]. Tumour-promoting inflammation is also regarded as a hallmark of cancer, and it has a vital role in the formation and maintenance of tumour architecture [3]. The cytokines and chemokines produced by cancer cells as well as non-cancer and immune cells have pro-tumour and antitumour roles, and their complex interaction and signalling within the tumour microenvironment determines the fate of cancer [4]. The pro-inflammatory cytokines produced as an outcome of inflammatory processes lead to immunosuppression, promotion of angiogenesis, invasion and metastasis [5]. Cytokines such as TNF-α and IL-1 aggravate angiogenesis via upregulation of vascular endothelial growth factor (VEGF) by modulating various chemokine receptor signalling pathways and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway [6]. Inflammasomes are multiprotein complexes that respond to well-known markers of both exogenous and endogenous cellular stress. They identify different cellular stressors through specialized receptors, and lead to cleavage and subsequent activation of IL-1β and IL-18 and induction of inflammatory pyroptotic cell death by regulating the activation of caspase-1 [7]. The role of inflammasomes has been well characterized in various inflammatory diseases, infections, and autoimmune conditions. However, in the case of cancer, the role of inflammasomes has remained controversial for years. This is because of the differential roles played by these protein complexes in different cancer models. Inflammasomes and their components have been well reported to be involved in the progression of cancer, including lung, oral and head and neck squamous cell carcinomas [8], [9], [10], [11]. However, contrasting reports also indicate the tumour-suppressive role of inflammasomes in the development and progression of some cancers, such as colorectal cancer [12]. Hence, the complex role of inflammasomes in oncology demands closer attention.
Epigenetic events such as DNA methylation, histone modification and posttranscriptional alteration of gene expression through noncoding RNAs have important roles during cancer progression [13], [14], [15]. Furthermore, epigenetic regulation modulates the expression of genes encoding inflammasome components during various diseases [16]. Here, we discuss the epigenetic events regulating the expression of inflammasome components and their respective roles in cancer. In addition, we analyse the interconnection between autophagy and inflammasomes from a cancer perspective. Autophagy is a conserved catabolic process that helps in the maintenance of cellular homeostasis in a variety of stress conditions and has a promising role in diverse diseases [17]. Autophagy also acts as a regulator during inflammation, checking hyperactivation of inflammatory responses and inducing a steady response [18]. However, the role of autophagy in cancer is controversial due to its stage-specific behaviour during cancer progression [19], [20]. Moreover, both the inflammasome and autophagy have critical roles in the recognition and eradication of cellular stresses and the protection of cells and their normal physiological processes. Recent studies also depict autophagy as a key factor regulating inflammasome activation and its consequences in the tumour microenvironment. Interestingly, increasing studies on various phytotherapeutic approaches to modulate autophagic regulation of inflammasomes from a cancer perspective have emerged recently. This review provides a comprehensive summary of the epigenetic and autophagic regulatory mechanisms of inflammasome activation during cancer initiation, progression and malignant transformation and is useful for exploring new therapeutic targets in cancer.
Section snippets
Inflammasomes: structure, activation and consequences
Inflammasomes are a type of protein complex that play an essential role in the maintenance of cellular homeostasis during stress by regulating immunity and inflammation. The stress may be tissue damage, metabolic imbalance, pathogen invasion or any type of infection. These multimeric protein complexes generally consist of three parts: a sensor, an adaptor (that is, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC)) and an effector (that is,
Role of inflammasomes in tumour progression
Deregulated inflammatory responses have a significant influence on tumour initiation and progression by providing a continuous supply of growth factors for limitless replication and DNA damaging agents for permanent genomic instability [40]. Transcription factors such as NF-κB and STAT3, when activated by extrinsic or intrinsic inducers, lead to activation and accumulation of several factors supporting aberrant inflammation, immune suppression and tumour promotion [41], [42], [43], [44].
Tumour-suppressive role of NLR family inflammasomes
The tumour-suppressive role of inflammasomes has been widely explored in colorectal cancer models. Mice lacking NLRP3 or caspase-1 are more susceptible to azoxymethane (AOM) and dextran sodium sulfate (DSS) induced colitis-associated cancer (CAC) than wild-type mice, suggesting a protective role of NLRP3 inflammasomes in CAC. In these cases, increased cancer progression correlates with a decrease in IL-18 and IL-1β levels within the tumour microenvironment [72]. In colorectal cancer, decreased
Epigenetic regulation of inflammasome components and their role in cancer
Epigenetics in general refers to stable inheritable alterations in gene expression without changes to the DNA sequence. Major epigenetic changes, including DNA methylation, modification of histones and posttranscriptional modification through noncoding RNAs, have been well studied for their vital role in regulating the expression of key genes during cancer progression. DNA methylation is the addition of a methyl group to the cytosine residue at the C5 position mostly within CpG dinucleotides by
Autophagy and inflammasomes: what is the connection?
Autophagy is an evolutionarily conserved catabolic process for the degradation of damaged cytoplasmic parts and dysfunctional organelles in a lysosome-dependent manner. The vital role of autophagy in the maintenance of cellular homeostasis is evident in a variety of stress conditions [118]. The complete autophagic process of cellular recycling can be divided into four steps: phagophore initiation, elongation and maturation, autophagosome formation and cargo degradation. Initiation of the
Epigenetic reprogramming and autophagy modulation to influence inflammasomes in cancer and possible therapy
Inflammasome activation has a multifaceted impact on cancer progression, and epigenetic and autophagic modulation of inflammasomes could have potential implications in cancer treatment. Aberrant epigenetic modifications are associated with the silencing of genes encoding various inflammasome components. For example, promoter hypermethylation of the ASC gene is a useful marker for prostate cancer carcinogenesis, and pharmacological demethylation of ASC could be a novel therapeutic intervention
Conclusion and perspective
The role of the inflammasome in cancer is questionable. On the one hand, inflammasome activation contributes to cancer growth, progression and metastasis in lung, breast, skin, oral, and head and neck cancers by inducing tumour-promoting inflammation; on the other hand, inflammasomes have been reported to restrict cancer cell survival by promoting pyroptotic cell death, bringing an effective immune response and maintaining proper tissue homeostasis in inflammation-associated colorectal cancers.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
Research support was partly provided by the Department of Biotechnology [BT/PR23304/MED/30/1823/2017], Ministry of Science and Technology, Government of India. SRM acknowledge Department of Biotechnology, Government of India for providing fellowship.
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