Anticancer Activity of Pristimerin in Epidermal Growth Factor Receptor 2-Positive SKBR3 Human Breast Cancer Cells

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  • Lee Jin Sun
    Department of Surgery, Chungnam National University Hospital
  • Yoon In Sang
    Department of Surgery, Chungnam National University Hospital
  • Lee Myung Sun
    Surgical Oncology Research Laboratory, Regional Cancer Institute, Chungnam National University Hospital
  • Cha Eun Young
    Surgical Oncology Research Laboratory, Regional Cancer Institute, Chungnam National University Hospital
  • Thuong Phuong Thien
    Vietnam National Institute of Medicinal Materials
  • Diep Trinh Thi
    Vietnam National Institute of Medicinal Materials
  • Kim Je Ryong
    Department of Surgery and Research Institute for Medicinal Sciences, College of Medicine, Chungnam National University Department of Surgery, Chungnam National University Hospital

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Pristimerin is a naturally occurring triterpenoid that causes cytotoxicity in several cancer cell lines. However, the mechanism of action for the cytotoxic effect of pristimerin has not been unexplored. The purpose of this study was to investigate the effect of pristimerin on cytotoxicity using the epidermal growth factor receptor 2 (HER2)-positive SKBR3 human breast cancer cell line. Pristimerin inhibited proliferation in dose- and time-dependent manners in cells. We found it to be effective for suppressing HER2 protein and mRNA expression. Fatty acid synthase (FASN) expression and FASN activity were downregulated by pristimerin. Adding of exogenous palmitate, the end product of de novo fatty acid synthesis, reduced the proliferation activity of pristimerin. The changes in HER2 and FASN expression induced by pristimerin altered the levels of Akt and mitogen-activated protein kinase (MAPK) phosphorylation (Erk1/2, p38, and c-Jun N-terminal kinase (JNK)). Pristimerin lowered the levels of phosphorylated mammalian target of rapamycin (mTOR) and its downstream targets such as phosphoprotein 70 ribosomal protein S6 kinase and 4E binding protein1. Pristimerin inhibited migration and invasion of cells, and co-treatment with the mTOR inhibitor rapamycin additionally suppressed these activities. Pristimerin-induced apoptosis was evaluated using Western blotting for caspase-3, -8, -9, and poly (ADP-ribose) polymerase expression and flow cytometric analysis for propidium iodide labeling. These results suggest that pristimerin is a novel HER2-downregulated compound that is able to decrease fatty acid synthase and modulate the Akt, MAPK, and mTOR signaling pathways to influence metastasis and apoptosis. Pristimerin may be further evaluated as a chemotherapeutic agent for HER2-positive breast cancers.

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