Intestinal BCRP requires JAK3 activity for drug efflux and barrier functions in obesity

Significance

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.

About the author

Dr. Jayshree Mishra is a Research Assistant Professor at the College of Pharmacy at Texas A&M University. Dr. Mishra has received her PhD in Microbial Biotechnology, post-doctoral training from College of Medicine UT-HSC Memphis, TN and TAMU-College of Pharmacy in gastrointestinal physiology. Her research aims to understand the molecular and cellular mechanism underlying obesity-associated conditions and elucidates how the obese patients have compromised intestinal innate immune functions. Recent studies from her lab have revealed obesity as a cause of xenobiotic stress and associated complications.

Dr. Mishra’s work elucidated how drug efflux and barrier functions are compromised during obesity through post-translation regulation of one of the intestinal protein BCRP by a non –tyrosine kinase enzyme; Janus kinase 3. These studies have wider implications not only in our understanding of physiological and pathophysiological mechanisms of intestinal chronic-low-grade inflammation-associated diseases but also in protein-mediated drug efflux pharmacokinetic and pharmacodynamic characteristics of oral drug formulations.

Dr. Mishra has received many national and international awards (Jawaharlal Nehru Fellowship award; India, DAAD Fellowship; Germany, research grant from Vishal Raju Bhagat Foundation, NIH –SBIR, PESCA grant from Texas A&M, ABRACM Faculty Judge award) and authored many research articles and abstracts to her credit.

About the author

Dr. Narendra Kumar is a tenured Associate Professor in the College of Pharmacy at the Texas A&M University. He has a PhD in Biotechnology, and a postdoctoral training in gastrointestinal physiology from the UT-HSC Memphis. He teaches Immunology, Biochemistry, Pharmacogenomics, and pathophysiology of autoimmune diseases under professional PharmD program. In research, he is the recipient of over 28 different awards of nationa/international repute including Crohn’s and Colitis Foundation of America (CCFA) Research Fellowship Award, CCFA Career Development Award, National Institute of Health (NIH) Career Development Award (K01), NIH small business innovation research award (SBIR), American Gastroenterology Association (AGA) Research Scholar Award to name a few. He has three patents to his credit, His group has published over 100 abstracts and peer reviewed research articles where some of his articles have been cited over 400 times. He has also authored two book chapters. His research interest include chronic inflammatory diseases including IBD, Alzheimer’s and obesity.

About the author

Dr. Randall Simonsen attended University of Pittsburgh Medical School and pathology residency program, afterward joining the faculty at the University of Texas Southwestern Medical School as assistant professor. He was medical director of National Health Laboratory in Houston Texas, and currently medical director of three Hospital labs in south Texas.

Reference

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.

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