Elevated BCRP Transporter and Altered NF-кB Pathway Mediate Zoledronic Acid Resistance in MCF-7 Cells

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Zoledronic acid (ZA), a bisphosphonate, is a standard treatment for bone preservation in cancer.
• ZA exerts anti-cancer effects via intracellular signaling pathways like NF-κB, inhibiting proliferation and inducing apoptosis.
• Acquired resistance to ZA poses a significant clinical challenge.

Purpose of the Study:

• To investigate the mechanisms of ZA resistance in MCF-7 breast cancer cells.
• To examine the role of the human breast cancer resistance protein (BCRP) and NF-κB pathway in ZA resistance.
• To assess epithelial-mesenchymal transition (EMT) markers in ZA-resistant cells.

Main Methods:

• MCF-7 cells were stepwise selected for resistance to ZA, creating MCF-7/Zol cells.
• BCRP expression and localization were analyzed.
• NF-κB pathway activation (phosphorylated IκB, nuclear translocation) was assessed.
• EMT markers were evaluated in parental and resistant cells.

Main Results:

• MCF-7/Zol cells exhibited elevated BCRP levels with altered intracellular localization.
• Increased BCRP activity led to decreased substrate accumulation in resistant cells.
• ZA-resistant cells showed increased phosphorylated IκB and nuclear NF-κB translocation.
• No significant changes in EMT markers were observed in MCF-7/Zol cells.

Conclusions:

• Upregulation of BCRP and activation of the NF-κB pathway are key mechanisms of ZA resistance in MCF-7 breast cancer cells.
• BCRP-mediated efflux and NF-κB signaling contribute to ZA resistance.
• EMT is not a primary mechanism of ZA resistance in this model.
• Understanding these resistance mechanisms is crucial for developing strategies to overcome drug resistance and identify biomarkers for multidrug resistance (MDR).