Ginsenoside panaxatriol reverses TNBC paclitaxel resistance by inhibiting the IRAK1/NF-κB and ERK pathways

Panpan Wang; Dan Song; Danhong Wan; Lingyu Li; Wenhui Mei; Xiaoyun Li; Li Han; Xiaofeng Zhu; Li Yang; Yu Cai; Ronghua Zhang

doi:10.7717/peerj.9281

Ginsenoside panaxatriol reverses TNBC paclitaxel resistance by inhibiting the IRAK1/NF-κB and ERK pathways

PeerJ. 2020 Jun 3:8:e9281. doi: 10.7717/peerj.9281. eCollection 2020.

Authors

Panpan Wang^#^{1

2}, Dan Song^#¹, Danhong Wan³, Lingyu Li³, Wenhui Mei³, Xiaoyun Li³, Li Han², Xiaofeng Zhu², Li Yang¹, Yu Cai^{1

4}, Ronghua Zhang^{1

4}

Affiliations

¹ College of Pharmacy, Jinan University, Guangzhou, China.
² First Affiliated Hospital of Jinan University, Guangzhou, China.
³ College of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
⁴ Cancer Research Institute, Jinan University, Guangzhou, China.

^# Contributed equally.

Abstract

Background: Paclitaxel (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.

Methods: CellTiter-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.

Results: We 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.

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.

Keywords: ERK pathway; Ginsenoside panaxatriol; IRAK1/NF-κB pathway; Paclitaxel resistance; TNBC.

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81603342) and the Administration of Traditional Chinese Medicine of Guangdong Province (No. 20171074). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.