Modulating drug resistance by targeting BCRP/ABCG2 using retrovirus-mediated RNA interference

Area of Science:

• Molecular biology
• Cancer research
• Drug discovery

Background:

• The Breast Cancer Resistance Protein (BCRP/ABCG2) transporter facilitates drug resistance in various cells by utilizing ATP hydrolysis for energy.
• Targeting BCRP/ABCG2 is crucial for overcoming multidrug resistance in cancer therapy.

Purpose of the Study:

• To develop and screen efficient RNA interference agents targeting the ATP-binding domain of BCRP/ABCG2.
• To investigate the potential of these agents in reversing drug resistance and enhancing cancer cell sensitivity.

Main Methods:

• Construction and packaging of pLenti6/BCRPsi shRNA recombinant retroviruses targeting specific sequences in the BCRP/ABCG2 ATP-binding domain.
• Screening of retroviruses (V-BCRPi) for significant knockdown effects using drug-sensitivity assays and flow cytometry.
• In vivo studies using a mouse xenograft model (JAR cytoma) to assess BCRP/ABCG2 expression and drug response post-V-BCRPi treatment.

Main Results:

• V-BCRPi retroviruses demonstrated significant knockdown of BCRP/ABCG2 expression in tumor tissues.
• Treatment with V-BCRPi increased the sensitivity of tumor cells to 5-fluorouracil (5-FU).
• V-BCRPi enhanced the apoptosis-promoting effects of 5-FU in the tumor microenvironment.

Conclusions:

• A novel RNA interference recombinant retrovirus (V-BCRPi) was successfully developed to inhibit BCRP/ABCG2 function by targeting its ATP-binding domain.
• This study presents a new strategy for improving chemo-sensitivity in breast cancer and other tumors.
• The findings support the potential application of V-BCRPi in gene therapy and functional studies of malignant tumors.