Inflammasomes in cancer: a double-edged sword

Abstract

Chronic inflammatory responses have long been observed to be associated with various types of cancer and play decisive roles at different stages of cancer development. Inflammasomes, which are potent inducers of interleukin (IL)-1β and IL-18 during inflammation, are large protein complexes typically consisting of a Nod-like receptor (NLR), the adapter protein ASC, and Caspase-1. During malignant transformation or cancer therapy, the inflammasomes are postulated to become activated in response to danger signals arising from the tumors or from therapy-induced damage to the tumor or healthy tissue. The activation of inflammasomes plays diverse and sometimes contrasting roles in cancer promotion and therapy depending on the specific context. Here we summarize the role of different inflammasome complexes in cancer progression and therapy. Inflammasome components and pathways may provide novel targets to treat certain types of cancer; however, using such agents should be cautiously evaluated due to the complex roles that inflammasomes and pro-inflammatory cytokines play in immunity.

Figure 1

Inflammasome activation and signaling. (A) Inflammasomes are activated in two steps. First, priming induces the expression of pro-IL-1β and pro-IL-18 through the activation of NF-κB. NF-κB is activated by TNF-α and IL-1 or through sensing of “danger signals” (PAMPs and DAMPs) by TLRs or NOD1/2. Priming also readies the inflammasomes for activation through other unknown mechanism. The second step involves the sensing of PAMPs and DAMPs by NLRs (NLRP3, NLRC4, etc.) or AIM2 through mechanisms that are not fully understood. Some NLRs, such as NLRP3 and NLRC4, interact with pro-caspase-1 through ASC, while others, such as NLRP1 can interact directly with caspase-1. Activation of NLRs results in the activation of pro-caspase-1, which when cleaved can catalyze the proteolytic cleavage and activation of IL-1β and IL-18. Activation of caspase-1 can also induce pyroptotic cell death, though cleavage of caspase-1 is not required for this process. (B) Non-canonical inflammasomes involve activation of caspase-8 and caspase-11 which can lead to induction of pyroptosis, apoptosis and activation of IL-1β