Inflammasome as a Therapeutic Target for Cancer Prevention and Treatment

Abstract

Chronic inflammation is a critical modulator of carcinogenesis through secretion of inflammatory cytokines, which leads to the formation of an inflammatory microenvironment. In this process, the inflammasome plays an important role in the expression and activation of interleukin (IL)-1β and IL-18 to promote cancer development. The inflammasome is a multiprotein complex consisting of several nucleotide-binding domain and leucine-rich repeat containing receptor, adaptor proteins, and caspase 1 (CASP1). It senses the various intracellular (damage-associated molecular patterns) and extracellular (pathogen-associated molecular patterns) stimuli. A primed inflammasome recruits adaptor proteins, activates CASP1 to enhance the proteolytic cleavage of pro-IL-1β and IL-18, and sends the signal to respond to each insult. Depending on stimuli and cell contexts, several inflammasomes are closely associated with the initiation and promotion of carcinogenesis. In contrast, inflammasomes also show an ambivalent effect on carcinogenesis by enhancing inflammatory cell death (pyroptosis) and repairing damaged tissues. Although the inflammasome plays a controversial role in carcinogenesis, it may be a promising target for human cancer prevention and treatment. A more in-depth study on the role of the inflammasome in carcinogenesis, based on stimuli, cell contexts, and cancer stages, can lead to the development of novel therapeutic strategies against malignant human cancers.

Keywords: Cancer; Inflammasomes; NLR proteins; Therapeutics.

Figure 1

Protective roles of the inflammasome in cancer. Nucleotide-binding domain and leucine-rich repeat containing receptor Family Pyrin Domain Containing 3 (NLRP3) and NLRP6 regulate the induction of interleukin (IL)-18, supporting a protective role of inflammasome against colorectal cancer. IL-18 suppresses the expression of IL-22 and inhibits intestinal carcinogenesis at late stages. The NLRP3 inflammasome-mediated IL-18 production is required for the maturation of hepatic natural killer (NK) cells to enhance immunosurveillance against metastasis of colonic tumor cells into the liver. NLRP6-IL-18 axis is also involved in the maintenance of intestinal homeostasis and protection against colitis. Nucleotide-binding domain and leucine-rich repeat containing receptor family CARD domain containing 4 (NLRC4) suppresses colorectal cancer and melanoma through the enhancement of epithelial cell apoptosis and T cell activation. NLRP12 plays a role as tumor suppressor through the regulation of NF-κB signaling, leading to the modulation of inflammatory signaling.

Figure 2

Pro-tumorigenic roles of the inflammasome in cancer. The nucleotide-binding domain and leucine-rich repeat containing receptor Family Pyrin Domain Containing 3 (NLRP3)-mediated interleukin (IL)-1β signaling suppresses the tumoricidal activity of natural killer (NK) and T cells to promote lung metastasis and mesothelioma. NLRP3-IL-1β axis results in the migration of myeloid-derived suppressor cells (MDSCs) to tumorigenic sites and promotes the gastric cancer. Overexpression of interferon (INF)-γ by absent in melanoma 2 (AIM2) and NLRP3 also enhances Janus kinase (JAK)/STAT signaling to promote the colon cancer. NF-κB signaling activated by the nucleotide-binding domain and leucine-rich repeat containing receptor family apoptosis inhibitory protein (NAIP) inflammasome is involved in the promotion of prostate cancer through the induction of chronic inflammation.