Targeting the NLRP3 Inflammasome as a New Therapeutic Option for Overcoming Cancer

Abstract

Inflammasomes are multiprotein complexes that regulate the maturation and secretion of the proinflammatory cytokines interleukin-1beta (IL-1β and interleukin-18 (IL-18) in response to various intracellular stimuli. As a member of the inflammasomes family, NLRP3 is the most studied and best characterized inflammasome and has been shown to be involved in several pathologies. Recent findings have made it increasingly apparent that the NLRP3 inflammasome may also play a central role in tumorigenesis, and it has attracted attention as a potential anticancer therapy target. In this review, we discuss the role of NLRP3 in the development and progression of cancer, offering a detailed summary of NLRP3 inflammasome activation (and inhibition) in the pathogenesis of various forms of cancer. Moreover, we focus on the therapeutic potential of targeting NLRP3 for cancer therapy, emphasizing how understanding NLRP3 inflammasome-dependent cancer mechanisms might guide the development of new drugs that target the inflammatory response of tumor-associated cells.

Keywords: NLRP3 inflammasome; inflammation; inhibitors; target-therapy.

Figure 1

NLRP3 inflammasome priming and activation. The activation process of the NLRP3 inflammasome requires two main signals: (i) signal 1 (priming), which leads to the activation of the transcription factor NF-kappaB and the subsequent transcription of canonical and noncanonical NLRP3 inflammasome components; and (ii) signal 2 (activation), which is responsible for NLRP3 complex assembly and the subsequent release of inflammatory cytokines (IL-1β and IL-18). Priming is provided by exposure to pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) or by endogenous cytokines that activate receptors at the cell membrane. The induction of NLRP3 expression during priming is controlled by FAS-associated death domain protein (FADD) and caspase-8. NLRP3 activation is provided by a plethora of stimuli, such as PAMPs or damage-associated molecular patterns (DAMPs), ATP, and viral RNA, that in turn trigger downstream signaling events such as mitochondrial damage, mitochondrial ROS production, lysosomal disruption, and ion (K⁺ and Ca²⁺) efflux. Mitochondrial antiviral signaling protein (MAVS) mediates the NLRP3 activation induced by RNA viruses. Excessive Ca²⁺ released from the ER causes mitochondrial dysfunction and is implicated in NLRP3 inflammasome activation. Chloride intracellular channel protein (CLIC)-mediated Cl^- efflux promotes the NEK7-NLRP3 interaction and subsequent NLRP3 inflammasome assembly. LPS can directly activate TLR4 to induce the transcription and activation of caspase-11, which in turn cleaves the pore-forming protein gasdermin D (GSDMD), which can induce pyroptosis. IL-18: interleukin-18; IL-1β: interleukin-1beta; IL-1R: interleukin 1 receptor; mt-DNA: mitochondrial DNA; ROS: reactive oxygen species; TLR: Toll-like receptor. Created with BioRender.com accessed on 30 March 2021.

Figure 2

NLRP3 inflammasome involvement in distinct types of cancer.