NLRP6 targeting suppresses gastric tumorigenesis via P14^ARF–Mdm2–P53-dependent cellular senescence

Abstract

NLRP6, a member of the Nod-like receptor family, protects against chemically induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms involved in this NLRP6-mediated protection remain unclear. Here, we show that NLRP6 was down-regulated in approximately 75% of primary gastric cancer cases and exhibited significant associations with advanced clinical-stage lymph node metastasis and poor overall survival. Functional studies established that ectopic overexpression or down-regulation of NLRP6 inhibited cancer cell proliferation by inducing cell cycle arrest at the G1 phase via P21 and Cyclin D1 both in vitro and in vivo. Activation of the P14ARF-P53 pathway played a crucial role in the observed cellular senescence. We further demonstrated that ectopic overexpression of NLRP6 combined with inactivation of NF-κB(p65) and Mdm2 activates P14ARF-P53 to promote the senescence of gastric cancer cells. These findings indicate that NLRP6 functions as a negative regulator of gastric cancer and offer a potential new option for preventing gastric cancer.

NOD-like receptors: major players (and targets) in the interface between innate immunity and cancer

“…H. pylori infection suppresses miR-22, increasing NLRP3 expression which, in turn, leads to IL-1β secretion and promotes the proliferation of epithelial cells and GC tumorigenesis [190]. Contrarily, it has been reported that NLRP6 expression is reduced in ∼75% of the primary GC cases, and is associated with lymph node metastasis and poor overall survival [191]. NLRP6 expression may suppress cancer cell proliferation by inducing senescence in a mechanism mediated by p21 and cyclin D1.…”

“…NLRP6 expression may suppress cancer cell proliferation by inducing senescence in a mechanism mediated by p21 and cyclin D1. In fact, overexpression of NLRP6 , along with the inactivation of NF-κB and Mdm2, activates the p14ARF-p53 pathway and promotes senescence of GC cells [191]. This particular mechanism may be potentially explored for the GC treatment.…”

“…Approximately 2–3 million skin cancers cases are diagnosed each year and their incidence has increased over the last decades [207]. Skin tumors can be classified as non-melanomas (derived from keratinized epithelial cells) or melanomas (derived from melanocytes) [190,191]. Melanoma accounts for 2% of the cases, being the most aggressive type of skin cancer, accounting for almost 10000 deaths per year [207,208].…”

Harnessing innate immune pathways for therapeutic advancement in cancer

“… 449 NLRP3 Gastric cancer Xenograft murine model of BGC-823 Macrophage; epithelial cells; Tumor cells Pro The activation of the NLRP3 inflammasome promotes epithelial cell proliferation and gastric cancer tumorigenesis through IL-1β and the enhancement of cyclin-D1 transcription. 436 NLRP6 Gastric cancer Xenograft murine model of MKN45 Tumor cells Anti NLRP6 promotes the senescence of gastric cancer cells through the activation of the P14ARF–Mdm2–P53 pathway 442 NLRP12 Colorectal cancer; Spontaneous murine model induced by azoxymethane and dextran sodium sulfate; Myeloid cells; epithelial cells; Tumor cells Anti NLRP12 serves as a negative regulator of non-canonical NFκB and MAPK-mediated inflammation, thereby inhibiting inflammation-induced colorectal cancer. 429 RIG-I HCC Spontaneous murine model induced by DEN Tumor cells Anti RIG-I amplifies the IFN-JAK-STAT signaling pathway by enhancing the activation of STAT1, leading to the induction of apoptosis in tumor cells.…”

Heat Shock Protein 90 as Therapeutic Target for CVDs and Heart Ageing

“…p14ARF functions as a stabiliser of p53 (tumour suppressor protein) and regulator of CDK4, thus controlling cell cycle G1 progression [ 92 ]. The close association between p14ARF and p53 was shown to play a crucial role in the cellular senescence of cancer cells [ 93 ]. Additionally, p14ARF binds Mdm2 protein, the proto-oncogenic E3 Ubiquitin-Protein Ligase, known to target tumour suppressor proteins for proteasomal degradation.…”