Mechanistic insight into anti-cancer activity of plumbagin in endocrine resistant and HER2-overexpressed breast cancer cells

Abstract

Abstract Background Plumbagin (PLB) is a naphthoquinone compound isolated from the root of Plumbago indica. In our previous study reported that PLB was able to inhibit cell growth in estrogen receptor (ER)-positive and endocrine resistant cells in vitro. The overexpression of human epidermal growth factor receptor 2 (HER2) and nuclear receptor coactivator 3 (NCOA3) was reported in endocrine resistant cells. However, the molecular mechanism underlying of inhibitory effect of PLB remains to be elucidated. We further investigated the mechanisms of PLB on cell apoptosis and HER2 signaling in endocrine resistant and HER2-overexpressing breast cancer. Methods The experiments were performed on MCF-7/LCC9 (endocrine resistant) and SKBR3 (HER2-overexpressing) cell lines. Basal levels of HER2 downstream signaling and NCOA3 in cancer cells used this study were determined by quantitative PCR (qPCR) and western blot. Functional and molecular studies of PLB included cell proliferation and apoptosis were evaluated by colony-forming assay, flow cytometry, qPCR and western blot analyses. Results PLB significantly inhibited the proliferation of MCF-7/LCC9 and SKBR3 cells in a concentration-dependent manner. PLB dramatically induced apoptosis in both cell lines and reduced apoptosis-related gene expression. NCOA3 mRNA and AKT phosphorylation significantly reduced in MCF-7/LCC9 cells after treatment with PLB. PLB also decreased phosphorylation of SKBR3 cells. Conclusions These findings demonstrated the NCOA3 and AKT signaling might be involved in anti-cancer mechanism of PLB in endocrine resistant HER2-overexpressed breast cancer, supporting further investigations on the therapeutic potential of PLB in animal model and/or phase I clinical trials. Legal entity responsible for the study The authors. Funding Ratchadaphiseksomphot Endowment Fund (RA62/034 to W.K.) and Special Task Force for Activating Research (STAR) Ratchadaphiseksomphot Endownment Fund to Overcoming Cancer Drug Resistance Research Group. Disclosure All authors have declared no conflicts of interest.