Chronic exposure of ErbB TKIs inhibits DRA expression and activity through an ERK/Elk-1/CREB/AP-1 dependent pathway

Hong Yang, Ru Xian Lin, Rafiquel Sarker, Mark Donowitz

Research output: Contribution to journalArticlepeer-review

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 pCREB, 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.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Oct 16 2020

Keywords

  • Activating protein 1 (AP-1)
  • CAMP response element-binding protein (CREB)
  • Cystic fibrosis transmembrane conductance regulator (CFTR)
  • Diarrhea
  • Down regulated in adenoma (DRA)
  • ETS like kinase 1 (Elk-1)
  • Extracellular-signal-regulated kinase (ERK)
  • The human erythroblastic oncogene B receptor tyrosine kinase inhibitor (ErbB TKI)

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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