Radixin knockdown improves the accumulation and efficiency of methotrexate in tumor cells.

Abstract

The plasma membrane localization of efflux transporters, such as multidrug resistance‑associated protein (MRP/ABCC), is governed by scaffold proteins, such as the ezrin/radixin/moesin (ERM) proteins. Reduction of the anchor function of ERM proteins in tumor cells may decrease the transport activity of efflux transporters, possibly leading to increased intracellular accumulation and efficiency of anticancer drugs as substrates of efflux transporters. The effect of the knockdown of ERM proteins was examined in multiple carcinoma cell lines on the transport activity of efflux transporters and on the intracellular accumulation and efficiency of methotrexate (MTX). Radixin knockdown in human liver cancer HepG2 cells, human lung carcinoma A549 cells, and human breast carcinoma MDA‑MB‑453 cells led to a significant reduction in the transport activity of multidrug resistance‑associated protein 2 (MRP2). The plasma membrane localization of MRP2 was significantly decreased by radixin knockdown in HepG2 cells. Increases in the accumulation and cytotoxicity of MTX in HepG2 cells treated with siRadixin were observed compared with control or siNegative. An in vivo study revealed that siRadixin treatment improved the efficiency of MTX in tumor‑bearing mice. In conclusion, the present study provides information on radixin as a target molecule for the modulation of MRP activity in tumor cells.

• Authors: Atsushi Kawase, Yuta Inoue, Sayaka Nakazaki, Erika Koizumi, Masahiro Iwaki
• Journal: Oncology reports (Oncol Rep) Vol. 42 Issue 1 Pg. 283-290 (Jul 2019) ISSN: 1791-2431 [Electronic] Greece
• PMID: 31115547 (Publication Type: Journal Article)

Chemical References

• ABCB1 protein, human
• ABCC2 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Cytoskeletal Proteins
• Membrane Proteins
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• radixin
• Methotrexate

Topics

• A549 Cells
• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (metabolism)
• Animals
• Cell Membrane (metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cytoskeletal Proteins (antagonists & inhibitors, genetics)
• Gene Knockdown Techniques
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, genetics, metabolism)
• Male
• Membrane Proteins (antagonists & inhibitors, genetics)
• Methotrexate (administration & dosage, pharmacology)
• Mice
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (metabolism)
• Neoplasm Proteins (metabolism)
• RNA, Small Interfering (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays