NLRP3 Inflammasome: A Possible Link Between Obesity-Associated Low-Grade Chronic Inflammation and Colorectal Cancer Development

Abstract

Emerging evidence reveals that adipose tissue-associated inflammation is a main mechanism whereby obesity promotes colorectal cancer risk and progression. Increased inflammasome activity in adipose tissue has been proposed as an important mediator of obesity-induced inflammation and insulin resistance development. Chronic inflammation in tumor microenvironments has a great impact on tumor development and immunity, representing a key factor in the response to therapy. In this context, the inflammasomes, main components of the innate immune system, play an important role in cancer development showing tumor promoting or tumor suppressive actions depending on the type of tumor, the specific inflammasome involved, and the downstream effector molecules. The inflammasomes are large multiprotein complexes with the capacity to regulate the activation of caspase-1. In turn, caspase-1 enhances the proteolytic cleavage and the secretion of the inflammatory cytokines interleukin (IL)-1β and IL-18, leading to infiltration of more immune cells and resulting in the generation and maintenance of an inflammatory microenvironment surrounding cancer cells. The inflammasomes also regulate pyroptosis, a rapid and inflammation-associated form of cell death. Recent studies indicate that the inflammasomes can be activated by fatty acids and high glucose levels linking metabolic danger signals to the activation of inflammation and cancer development. These data suggest that activation of the inflammasomes may represent a crucial step in the obesity-associated cancer development. This review will also focus on the potential of inflammasome-activated pathways to develop new therapeutic strategies for the prevention and treatment of obesity-associated colorectal cancer development.

Globular Adiponectin Inhibits Breast Cancer Cell Growth through Modulation of Inflammasome Activation: Critical Role of Sestrin2 and AMPK Signaling

“…Although various mechanisms, such as chronic inflammation, sex hormone deregulation, and adipokine pathophysiology, have been proposed for the linkage between adiposity and cancer [51,52], the underlying molecular mechanisms still remain poorly understood. Emerging evidence also reveals that adipose tissue-associated inflammation is a major mechanism by which obesity promotes metabolic disorders and cancer risk [53,54]. Therefore, the role of inflammasomes, a key player in inflammatory and immune responses, in regard to obesity-related diseases, has been being paid increasing attention.…”

Preventive Effects of Kaempferol on High-Fat Diet-Induced Obesity Complications in C57BL/6 Mice

“…Rat studies indicate that long-term intake of a high-fat diet (HFD) can lead to impaired lipid metabolism, as indicated by elevated total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels [4]. In addition to the disruption of lipid metabolism, low-grade chronic inflammation has been identified as a potential mechanism of obesity-related conditions [5].…”

Rab GTPase Mediating Regulation of NALP3 in Colorectal Cancer

“…However, the aberrant expression of NALP3 may result in severe intestinal inflammation, triggering the cyclical activation of the NALP3 inflammasome [ 8 ]. IL-1β and IL-18, the downstream signaling molecules from the NLRP3 pathway, have pleiotropic effects on CRC tumorigenesis [ 9 , 10 , 11 , 12 ]. Studies have indicated elevated expression of NALP3 inflammasome in CRC tumour tissue samples [ 13 , 14 , 15 , 16 ], and a positive correlation has been defined between NALP3 and distance metastasis [ 16 ].…”

“…Studies have indicated elevated expression of NALP3 inflammasome in CRC tumour tissue samples [ 13 , 14 , 15 , 16 ], and a positive correlation has been defined between NALP3 and distance metastasis [ 16 ]. However, several studies have also reported the effects of the low levels of the NALP3 inflammasome function on CRC development [ 17 , 18 ], which suggests that NALP3 inflammasome plays a balancing role in the regulation of inflammation [ 11 ].…”