Abstract
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.
Highlights
Efflux transporters (ETs) such as P-glycoprotein (P-gp, ABCB1), multidrug resistanceassociated protein (MRP, ABCC), and breast cancer resistance protein (BCRP, ABCG2)actively pump anti-cancer drugs out of cancer cells
Use of direct ET inhibitors is not necessarily a promising approach because of low efficacy and/or adverse effects, inhibition of ETs in cancer cells could help improve the intracellular accumulation of anti-cancer drugs
We evaluated activities of ETs and cytotoxicity by anti-cancer drugs after ERMbinding phosphoprotein of 50 kDa (EBP50) KD with siRNA
Summary
Efflux transporters (ETs) such as P-glycoprotein (P-gp, ABCB1), multidrug resistanceassociated protein (MRP, ABCC), and breast cancer resistance protein (BCRP, ABCG2). Actively pump anti-cancer drugs out of cancer cells. Increased expression and activities of ETs in cancer cells can lead to cancer drug resistance. Use of direct ET inhibitors is not necessarily a promising approach because of low efficacy and/or adverse effects, inhibition of ETs in cancer cells could help improve the intracellular accumulation of anti-cancer drugs. Modulation of ET activity in cancer cells could be a novel approach to more effective chemotherapy. We focused on using a scaffold protein as a target molecule for modulation of ET activity. Scaffold proteins, such as ezrin/radixin/moesin (ERM) proteins, and Na+ /H+
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