Allyl isothiocyanate upregulates MRP1 expression through Notch1 signaling in human bronchial epithelial cells

Abstract

Multidrug resistance associated protein-1 (MRP1) and Notch signaling are closely related and both play a critical role in chronic obstructive pulmonary disease (COPD) establishment and progression. The aim of our work was to test whether Notch1 is involved in allyl isothiocyanate (AITC) induced MRP1 expression. We used cigarette smoke extract (CSE) to simulate the smoking microenvironment in vitro. The results demonstrated that CSE led to apoptosis as well as reduced the expression of Notch1, Hes1, and MRP1, while AITC significantly reversed this downregulation. Transfected with Notch1 siRNA downregulated MRP1 expression and activity, aggravated the suppression effect by CSE, and abolished the AITC-induced Notch1, Hes1, and MRP1 expression. Validation of the correlation between Notch1 and MRP1 was implemented by gel-shift assays (electrophoretic mobility shift assay). The result revealed an interaction between a specific promoter region of MRP1 and the intracellular domain of Notch1. In conclusion, Notch1 signaling positively regulated MRP1 in 16HBE cells and AITC induced MRP1 expression and function may be attributed to Notch1 signaling. These findings show that Notch1 and MRP1 might have a potential protective effect in the COPD process and become a new therapeutic target for COPD or other lung diseases. It also provides a theoretical basis for the therapeutic effects of AITC.