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

Abstract

Paclitaxel has been used widely to treat breast cancer and other types of cancer. However, resistance is a major cause of failure for treatment and results in cancer progression. The present study investigated the association between paclitaxel resistance and the mesenchymal phenotype, using a model of primary breast cancer cells and employing four different cultures, two with an epithelial phenotype (MBCDF and MBCD17) and two with a mesenchymal phenotype (MBCDF-D5 and MBCD3). Epithelial-mesenchymal markers were evaluated by western blotting; MBCDF and MBCD17 cells expressed E-cadherin, SNAIL, Slug, and Twist, low levels of N-cadherin, but not vimentin. MBCDF-D5 and MBCD3 cells expressed N-cadherin, vimentin, and higher levels of SNAIL, and low levels of E-cadherin, Slug, and Twist. Cell viability was evaluated using a crystal violet assay after paclitaxel treatment; primary breast cancer cells with mesenchymal phenotype were resistant to paclitaxel compared with the epithelial primary breast cancer cells. Furthermore, using western blotting, it was revealed that mesenchymal cells had elevated levels of nuclear factor-κΒ (NF-κB) p65 and IκB kinase (IKK). Additionally, it was demonstrated that paclitaxel-induced degradation of the inhibitor of NF-κB, activation of NF-κB in a dose-dependent manner, and Bcl-2 and Bcl-xL upregulation. Finally, employing western blotting and crystal violet assays, the effects of the proteasome inhibitor ALLN were assessed. ALLN inhibited paclitaxel-induced NF-κB activation and restored the sensitivity to paclitaxel. Together, these data suggest that targeting the NF-κB/IKK axis might be a promising strategy to overcome paclitaxel resistance.

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“…Hitherto, transcription blockade was reported for PAs regarding the NFκB-pathway in HepG2 [ 61 ] and the HIF-1α-pathway in T47D [ 62 ], but none of the studies included TNBC. Both, the inflammation-associated NFκB pathway and the hypoxia-induced HIF-pathway, are triggered upon paclitaxel-based chemotherapy, and are involved in mediating chemoresistance [ 19 , 24 , 33 , 79 ]. Chemoresistance is a major feature of cancer stem cells (CSCs) that exhibit self-renewal and activation of several pathways that prevent apoptosis and drive tumor progression via growth and invasion [ 30 ].…”

“…Various NFκB activating stimuli, e.g., paclitaxel or the tumor necrosis factor α (TNFα), trigger the complex of IκB kinase (IKK)α/IKKβ/IKKϒ, which phosphorylates the IκBα/NFκB complex. Subsequently, IκBα is degraded via the proteasome and the p50/p65 dimer is released to translocate to the nucleus [ 18 , 19 ]. Among over 150 target genes, pro-inflammatory cytokines interleukin (IL) 6 and IL-8 maintain a positive feedback loop via NFκB to orchestrate tumor growth, metastasis, and drug resistance in an autocrine manner [ 20 , 21 ].…”

“…In particular, migration, as a crucial step in metastasis, is regulated by NFκB through the activation of transcription factors involved in the endothelial-to-mesenchymal transition (EMT) [ 22 ]. Moreover, inhibiting NFκB signaling is sufficient to suppress cancer cell migration and invasion [ 23 ] and to reverse paclitaxel resistance [ 19 ]. Thus, NFκB represents a promising target in TNBC.…”

“…Indeed, cancer stem cells are enriched in TNBC [ 31 ] and correlate with worse clinical outcome [ 32 ] due to their high capacity for self-renewal, enhanced metastasis, and chemotherapy resistance resulting in tumor relapse that is a major cause of therapy failure [ 30 ]. Paclitaxel is reported to enhance HIF and NFκB activity and, inversely, blocking both pathways could reduce chemotherapy resistance [ 19 , 24 , 33 ]. Thus, targeting NFκB and HIF may improve a patient’s outcome by targeting key processes for drug resistance.…”

“…Furthermore, a major role in tumor progression is attributed to the CAF-derived cytokines and growth factors that engage NFκB and HIF pathways [ 30 , 45 ], and correlate with cancer relapse and poor prognosis [ 32 ]. In a paracrine manner, diverse key pathways that are involved in cancer progression converge in NFκB signaling [ 46 ], which is a key pathway in mediating drug resistance [ 19 ]. Disrupting the interplay of stromal cells and TNBC through blocking NFκB suppresses paracrine signaling of cytokines IL-6 and IL-8 [ 23 , 47 ] and reduces tumor progression [ 14 , 42 ].…”