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

Atsushi Kawase1, Miho Hirosoko1, Yuka Sugihara1

  • 1Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan.

Pharmaceuticals (Basel, Switzerland)
|April 3, 2021
PubMed

Insights

This study shows that EBP50 knockdown in liver cancer cells reduces the activity of key drug efflux transporters, P-gp and MRP. A TAT-PDZ1 peptide was also found to modulate these transporter activities.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Increased expression of efflux transporters (ETs) is a major cause of drug resistance in cancer.
  • Scaffold proteins like ezrin/radixin/moesin (ERM) and NHERF1/EBP50 are involved in regulating cellular processes, including transporter activity.

Purpose of the Study:

  • To investigate whether EBP50 modulates ET activities in human liver cancer HepG2 cells.
  • To explore the potential of targeting EBP50-ET interactions for overcoming drug resistance.

Main Methods:

  • Utilized EBP50 siRNA for gene knockdown in HepG2 cells.
  • Employed a designed TAT-PDZ1 peptide to interfere with EBP50-ET interactions.
  • Measured intracellular accumulation of specific ET substrates: Rho123 (P-gp), CDF (MRP), and H33342 (BCRP).

Main Results:

  • EBP50 knockdown led to significantly higher intracellular accumulation of Rho123 and CDF, indicating decreased P-gp and MRP activity.
  • BCRP activity was not affected by EBP50 knockdown.
  • TAT-PDZ1 peptide treatment significantly increased CDF accumulation, suggesting modulation of MRP activity.

Conclusions:

  • EBP50 plays a role in modulating the activity of efflux transporters, specifically P-gp and MRP, in liver cancer cells.
  • This study is the first to report the use of a competitive peptide to modulate EBP50-MRP interactions.
  • Targeting EBP50 interactions presents a potential novel strategy for overcoming cancer multidrug resistance.
Keywords:
interactionpeptidescaffold proteintransporter

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