NLRP3 inflammasome in colitis and colitis-associated colorectal cancer.

A low level of inflammation is an integral part of the balance between the immune system and the microbiota in the high antigen environment of the gastrointestinal tract and maintains homeostasis. A failure of this balance can lead to chronic intestinal inflammation and increase the chances to develop colorectal cancer significantly. The underlying mechanisms that link inflammation and carcinogenesis are not clear but the molecular platforms of the inflammasomes have been implicated. Inflammasomes are molecule complexes that are assembled in response to microbial components or cellular danger signals and facilitate the production of bioactive pro-inflammatory cytokines. One inflammasome in particular, NLRP3, has been analysed extensively in its contribution to colitis and has been shown to be associated with the development of colitis-associated colorectal cancer. This review will summarise the role of NLRP3 in intestinal inflammation, discuss some of the triggers of inflammation in the gastrointestinal tract such as diet and introduce some opportunities to use this inflammasome as therapeutic target for the treatment of colitis and colitis-associated colorectal cancer.

Genetic alterations in Krebs cycle and its impact on cancer pathogenesis.

Cancer cells exhibit alterations in many cellular processes, including oxygen sensing and energy metabolism. Glycolysis in non-oxygen condition is the main energy production process in cancer rather than mitochondrial respiration as in benign cells. Genetic and epigenetic alterations of Krebs cycle enzymes favour the shift of cancer cells from oxidative phosphorylation to anaerobic glycolysis. Mutations in genes encoding aconitase, isocitrate dehydrogenase, succinate dehydrogenase, fumarate hydratase, and citrate synthase are noted in many cancers. Abnormalities of Krebs cycle enzymes cause ectopic production of Krebs cycle intermediates (oncometabolites) such as 2-hydroxyglutarate, and citrate. These oncometabolites stabilize hypoxia inducible factor 1 (HIF1), nuclear factor like 2 (Nrf2), inhibit p53 and prolyl hydroxylase 3 (PDH3) activities as well as regulate DNA/histone methylation, which in turn activate cell growth signalling. They also stimulate increased glutaminolysis, glycolysis and production of reactive oxygen species (ROS). Additionally, genetic alterations in Krebs cycle enzymes are involved with increased fatty acid ß-oxidations and epithelial mesenchymal transition (EMT) induction. These altered phenomena in cancer could in turn promote carcinogenesis by stimulating cell proliferation and survival. Overall, epigenetic and genetic changes of Krebs cycle enzymes lead to the production of oncometabolite intermediates, which are important driving forces of cancer pathogenesis and progression. Understanding and applying the knowledge of these mechanisms opens new therapeutic options for patients with cancer.