NLRP3, an emerging cancer treatment target
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NLRP3 inflammasome is a large intracellular polymeric protein complex formed in the cytosol, which can be produced due to the endogenous inflammatory immune response of cells. The formation of inflammasome can activate the inflammatory protease Caspase-1, thus promoting the maturation and release of inflammatory cytokines interleukin-1β (IL-1β) and IL-18, leading to the death of inflammatory cells (pyroptosis). Inflammation is the main sign of the occurrence and deterioration of cancer, and it affects cancer in various aspects, including proliferation, invasion, angiogenesis and metastasis. More importantly, the release of inflammatory factors mediated by various cells in the tumor microenvironment plays a key role in these processes. Since NLRP3 inflammasome is the innate immune center that mediates the secretion of proinflammatory cytokines, its interaction with other cell compartments plays a major role in regulating inflammatory response. However, it has been found that NLRP3 may play a dual role in the development of cancer - it can both promote and inhibit the occurrence of cancer. Its inhibitory effect is mainly reflected in colitis associated colorectal cancer (CAC), while its promoting effect is particularly obvious in other cancers, such as gastric cancer and skin cancer. In this article, we introduce some progress of NLRP3 inflammasome in cancer research.
Figure 1. Roles of NLRP3 in cancer
Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity 
PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. On May 4, 2020, a research team led by the University of Science and Technology of China and Fudan University found that PTEN protein in myeloid cells can improve anti-tumor immunity induced by chemotherapy by promoting the activation of NLRP3 inflammasome.
To explore the effect of PTEN on the activation of inflammasome at the cellular level, researchers used CRISPR/Cas9 gene editing technology to construct NLRP3-KO THP-1 cell line and NLRP3 point mutations (Y32E, T193E and T195E) THP-1 cell lines to simulate the dephosphorylation process of NLRP3, and determined the mechanism of PTEN promoting the activation of NLRP3 inflammasome by inducing the dephosphorylation of NLRP3 tyrosine in 32 locus.
Figure 2. PTEN mediated dephosphorylation of NLRP3 tyrosine in 32 locus is critical for the activation of inflammasome
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Crystalline silica particles cause rapid NLRP3-dependent mitochondrial depolarization and DNA damage in airway epithelial cells
Respirable crystalline silica can cause lung carcinomas. Researchers took silica as the research object and found that it can cause the activation of NLRP3 inflammasome and mitochondrial depolarization. Further study found that interference and knockout of NLRP3 could prevent mitochondrial depolarization and DNA damage induced by silica, and overexpression of NLRP3 gene in NLRP3-KO cells could induce such damage again. This shows that silica can induce DNA damage and double strand breaks in airway epithelial cells, providing direct evidence for the mechanism of action of respirable crystalline silica particles in inducing lung cancer, and revealing the key role of NLRP3 inflammasome in this process.
Figure 3. NLRP3 is critical to silica induced DNA damage
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NLRP3 inflammasomes in macrophages drive colorectal cancer metastasis to the liver
As a widely distributed effector of innate immunity, NLRP3 inflammasome affects development of many cancer types, but its exact role in colorectal cancer (CRC) is controversial. Researchers found that cells with the macrophage (MΦ) marker CD68 and strong NLRP3 expression densely surrounded CRC tissue. And further found that NLRP3 inflammasome was activated in MΦs by MΦ-CRC cell crosstalk. NLRP3 signaling activation in MΦs can contribute to CRC cell migration and invasion. To explore the role of NLRP3 in the proliferation and metastasis of CRC cells, researchers constructed SW480 and LoVo cell models of NLRP3-KO, and found that blocking NLRP3 signal transduction would inhibit the migration of CRC cells in vitro. This conclusion was also verified in the NLRP3-KO mouse model. Moreover, the researchers also found that the activation of NLRP3 signal can improve the migration and invasion ability of CRC cells. This series of experimental results support the idea that the development of NLRP-driven CRC.
Figure 4. NLRP3 knockout inhibits metastasis of colorectal cancer (CRC) cells
Both the promotion and inhibition of NLRP3 are of great significance to the research on the mechanism of the occurrence and development of cancer and the development of drug targets. NLRP3 may become a new target for cancer treatment, and in-depth research on the specific mechanism of its impact on the development of cancer is expected to provide a new direction for anti-cancer cancer drug discovery!
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Table 1. Promotional gene list
 Huang Y, Wang H, Hao Y, et al. Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity[J]. Nature Cell Biology, 2020, 22(6): 716-727.
 Wu R, Högberg J, Adner M, et al. Crystalline silica particles cause rapid NLRP3-dependent mitochondrial depolarization and DNA damage in airway epithelial cells[J]. Particle and fibre toxicology, 2020, 17(1): 1-20.
 Deng Q, Geng Y, Zhao L, et al. NLRP3 inflammasomes in macrophages drive colorectal cancer metastasis to the liver[J]. Cancer Letters, 2019, 442: 21-30.