NHERF1/EBP50 as a Target for Modulation of MRP Function in HepG2 Cells

Autor: Atsushi Kawase, Miho Hirosoko, Yuka Sugihara, Yunosuke Koyama, Ayaka Fukae, Hiroaki Shimada, Masahiro Iwaki
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Pharmaceuticals, Vol 14, Iss 3, p 239 (2021)
Druh dokumentu: article
ISSN: 1424-8247
DOI: 10.3390/ph14030239
Popis: As increased expression and activities of efflux transporters (ETs) often cause drug resistance in cancers, we tried modulating ET activity in cancer cells, using scaffold proteins such as ezrin/radixin/moesin (ERM) proteins, and Na+/H+ exchanger regulatory factor-1 (NHERF1)/ERM-binding phosphoprotein of 50 kDa (EBP50). To see whether EBP50 modulated ET activities in human liver cancer HepG2 cells, we used EBP50 siRNA and a designed TAT-PDZ1 peptide. The EBP50 knockdown (EBP50KD) cells had significantly higher intracellular accumulations of Rho123 and carboxy-dichlorofluorescein (CDF), but not H33342 (i.e., the respective substrates of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP)), compared with control HepG2, suggesting that EBP50 knockdown in HepG2 cells decreased activity of P-gp and MRP but not BCRP. Treatment with TAT-PDZ1 peptide (>1 pM) resulted in significantly higher CDF accumulation in HepG2 cells, which persisted for ≥180 min after TAT-PDZ1 peptide treatment. These results imply that EBP50 can modulate ET activities. To our knowledge, this is the first report on using a competitive peptide to modulate interactions between MRP and EBP50.
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