ABCG2/breast cancer resistance protein (BCRP) is a member of the adenosine triphosphate-binding cassette (ABC) transporter protein family. It is referred to as a ‘half-type’ ABC transporter, functions as a homodimer, and transports anticancer agents. It has been demonstrated that elevated BCRP levels result in resistance to anticancer drugs, including topotecan and irinotecan. Chronic low-grade inflammation obesity is primarily caused because of impaired intestinal barrier functions, however, the regulation of BCRP and its role in maintaining the intestinal barrier function are unknown.
Scientists from Texas A&M College of Pharmacy: Dr. Jayshree Mishra and Dr. Narendra Kumar together with Dr. Randall Simonson at Coastal Bend Pathology found a key role of Janus kinase 3 (Jak3), a non-receptor tyrosine kinase, in intestinal and systemic chronic low-grade inflammation (CLGI) associated obesity. Human obesity is a primary risk factor for metabolic syndrome and cancer, however, the underlying mechanisms of obesity associated with CLGI are unknown. The same research team reported in a previous study that compromised intestinal differentiation is a contributing factor for CLGI-associated obesity. In addition, dysfunctional intestinal barriers are associated with a number of chronic inflammatory conditions. The most recent study investigated the relationship between functional regulation of ABC family of drug transporter, BCRP during compromised intestinal barrier functions associated with obesity.
The researchers used a series of advanced molecular biology studies and reported that obese individuals have compromised intestinal BCRP function. They also showed that the loss of JAK3 mediated tyrosine phosphorylation of BCRP is the main cause of compromised BCRP functions. JAK3-mediated phosphorylation of BCRP promotes its interaction with membrane localized catenin which is important for barrier functions as well as BCRP surface localization and expression and also BCRP mediated intestinal drug efflux.
In their current study they observed in a study that during human obesity or JAK3 knockout in a study in mice intestinal JAK3 expression reduced. Similarly, colonic drug efflux and barrier functions are compromised and there is a significant loss of intestinal BCRP in human intestinal epithelial cells with siRNA catenin mediated knockdown. The results of the study further uncovered the mechanisms of BCRP-mediated intestinal drug efflux and barrier functions that prevent CLGI-associated obesity in both humans and mice by establishing a role for BCRP. The research work is published in JBC.
The study by Dr. Jayshree Mishra and colleagues explained the mechanism of BCRP dysfunction and supports the concept that BCRP not only is protective of xenotoxic compounds, but also protects from cascade of toxic or inflammatory events that leads to clinical diseases such as CLGI-associated obesity.
Mishra, J., Simonsen, R., & Kumar, N. (2019). Intestinal breast cancer resistance protein (BCRP) requires Janus kinase 3 activity for drug efflux and barrier functions in obesity. Journal of Biological Chemistry, 294(48), 18337-18348.Go To Journal of Biological Chemistry