Paclitaxel resistance is mediated by NF-κB on mesenchymal primary breast cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Paclitaxel is a key breast cancer therapeutic.
• Treatment failure due to paclitaxel resistance remains a significant clinical challenge.
• The epithelial-mesenchymal transition (EMT) is implicated in cancer progression and drug resistance.

Purpose of the Study:

• To investigate the association between the mesenchymal phenotype and paclitaxel resistance in primary breast cancer cells.
• To elucidate the underlying molecular mechanisms, particularly the role of the nuclear factor-kappa B (NF-κB) signaling pathway.

Main Methods:

• Utilized four primary breast cancer cell cultures: two epithelial (MBCDF, MBCD17) and two mesenchymal (MBCDF-D5, MBCD3).
• Evaluated epithelial-mesenchymal transition (EMT) markers via western blotting.
• Assessed cell viability using crystal violet assays post-paclitaxel treatment.
• Analyzed NF-κB pathway activation (p65, IKK) and downstream targets (Bcl-2, Bcl-xL) using western blotting.
• Investigated the effect of proteasome inhibitor ALLN on paclitaxel sensitivity and NF-κB activation.

Main Results:

• Mesenchymal cells (MBCDF-D5, MBCD3) exhibited resistance to paclitaxel compared to epithelial cells (MBCDF, MBCD17).
• Mesenchymal cells displayed higher expression of N-cadherin, vimentin, and SNAIL, with lower E-cadherin, Slug, and Twist.
• Paclitaxel treatment induced NF-κB activation in mesenchymal cells, evidenced by p65 and IKK elevation and degradation of NF-κB inhibitor.
• Paclitaxel treatment led to upregulation of anti-apoptotic proteins Bcl-2 and Bcl-xL in mesenchymal cells.
• The proteasome inhibitor ALLN suppressed paclitaxel-induced NF-κB activation and resensitized cells to paclitaxel.

Conclusions:

• The mesenchymal phenotype is associated with paclitaxel resistance in breast cancer.
• The nuclear factor-kappa B (NF-κB)/IκB kinase (IKK) signaling pathway plays a critical role in mediating paclitaxel resistance.
• Targeting the NF-κB/IKK axis represents a potential therapeutic strategy to overcome paclitaxel resistance in breast cancer.