Abstract
BackgroundPaclitaxel (PTX) resistance is a major obstacle in the treatment of triple-negative breast cancer (TNBC). Previously, we have reported that interleukin-1 receptor-associated kinase 1 (IRAK1) and its downstream pathways are associated with PTX resistance in TNBC cells. In this study, we sought to investigate the combination treatment of ginsenoside panaxatriol (GPT), one of the main active components in Panax ginseng, with PTX on viability and apoptosis of TNBC PTX resistant cells, and explore the role of IRAK1 mediated signaling pathways in the therapeutic effects.MethodsCellTiter-Glo and colony formation assays were used to assess cell viability. Flow cytometry was used to analyze subG1 and apoptosis. Western blot was used to detect expressions of proteins involved in apoptosis and the IRAK1/NF-κB and ERK pathways. The mRNA expression of inflammatory cytokines, S100A7/8/9 and cancer stem cell (CSC)-related genes were examined by qPCR. Stem cells were identified by tumor sphere assay. Cell invasion ability was examined by transwell assay.ResultsWe show that GPT inhibits MDA-MB-231 PTX resistant (MB231-PR) cell viability in a dose-dependent manner. When combined with PTX, GPT synergistically causes more cell death, induces subG1 accumulation and cell apoptosis. Besides, up-regulation of BAX/BCL-2 ratio, and down-regulation of MCL-1 are also observed. Moreover, this combination inhibits IRAK1, NF-κB and ERK1/2 activation, and leads to down-regulation of inflammatory cytokines (IL6, IL8, CXCL1, CCL2), S100A7/9 and CSC-related genes (OCT4, SOX2, NANOG, ALDH1, CD44) expression. In addition, the combination treatment suppresses MB231-PR cell invasion ability, and impairs tumor sphere growth both in MB231-PR and SUM159 PTX resistant (SUM159-PR) cells.ConclusionOur study demonstrates that GPT can resensitize TNBC PTX resistant cells to PTX by inhibiting the IRAK1/NF-κB and ERK pathways and reducing stem cell characteristics.
Highlights
Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer with poor prognosis (Foulkes, Smith & Reis-Filho, 2010)
By using gain and loss of function methods, we reported that activation of interleukin-1 receptor-associated kinase 1 (IRAK1), an upstream kinase of the NF-κB signaling pathway, is associated with PTX resistance in triple-negative breast cancer (TNBC) cells (Wee et al, 2015)
ginsenoside panaxatriol (GPT) promotes cytotoxicity of PTX in MB231-PR cells To explore whether GPT can promote cytotoxicity of PTX in TNBC resistant cells, MB231-PR was constructed and used as cell model
Summary
Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer with poor prognosis (Foulkes, Smith & Reis-Filho, 2010). Together with S100A7, S100A8 and S100A9 (S100A7/8/9), IRAK1 form a druggable circuitry which drives the malignancy of TNBC cells (Goh et al, 2017) These observations prompted us to search for potential candidate drugs that can target IRAK1 and its downstream signaling pathways. We sought to investigate the combination treatment of ginsenoside panaxatriol (GPT), one of the main active components in Panax ginseng, with PTX on viability and apoptosis of TNBC PTX resistant cells, and explore the role of IRAK1 mediated signaling pathways in the therapeutic effects. Up-regulation of BAX/BCL-2 ratio, and down-regulation of MCL-1 are observed This combination inhibits IRAK1, NF-κB and ERK1/2 activation, and leads to down-regulation of inflammatory cytokines (IL6, IL8, CXCL1, CCL2), S100A7/9 and CSC-related genes (OCT4, SOX2, NANOG, ALDH1, CD44) expression. Conclusion: Our study demonstrates that GPT can resensitize TNBC PTX resistant cells to PTX by inhibiting the IRAK1/NF-κB and ERK pathways and reducing stem cell characteristics
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