Chronic exposure of ErbB TKIs inhibits DRA expression and activity through an ERK/Elk-1/CREB/AP-1 dependent pathway
Yang, H.; Lin, R.-X.; Sarker, R.; Donowitz, M.
Show abstract
Diarrhea is the major side effect of first- and second-generation ErbB tyrosine kinase inhibitors (TKI), the mechanism of which remains incompletely understood. The current studies were carried out over the time frame that ErbB TKIs usually initiate diarrhea. We report in Caco-2/bbe cells that exposure of ErbB TKIs, but not non-ErbB TKIs for six days at clinically-relevant concentrations significantly reduced the expression of DRA and inhibited apical Cl-/HCO3-exchange activity. The ErbB TKIs decreased DRA expression through an ERK/Elk-1/CREB/AP-1 dependent pathway. The blockade of ERK phosphorylation by ErbB TKIs decreased the phosphorylation of Elk-1 and the amount of total and p-CREB, and reduced the expression of C-Fos, which is part of the AP-1 complex that maintain DRA expression. Altogether, our studies demonstrate that ErbB TKIs decrease expression and activity of DRA, which occurs over the time frame that these drugs clinically cause diarrhea, and since DRA is part of the intestinal neutral NaCl absorptive process, the reduced absorption is likely to represent a major contributor to the ErbB TKI-associated diarrhea.
Matching journals
The top 1 journal accounts for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- SLC35G1: A highly chloride-sensitive transporter responsible for the basolateral membrane transport in intestinal citrate absorption 94%
- Organoid-derived Duodenum Intestine-Chip for preclinical drug assessment in a human relevant system 93%
- Chemogenetic analysis of how receptors for short chain fatty acids regulate the gut-brain axis 92%
Similar papers in this journal
Similar papers in this journal
Similar papers in this journal
- Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 Spike protein 93%
- Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells 93%
- Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells. 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.