Down-Regulation of Human Epidermal Growth Factor Receptor 2/neu Oncogene by Corosolic Acid Induces Cell Cycle Arrest and Apoptosis in NCI-N87 Human Gastric Cancer Cells

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  • Lee Myung Sun
    Regional Cancer Institute, Chungnam National University Hospital
  • Cha Eun Young
    Regional Cancer Institute, Chungnam National University Hospital
  • Thuong Phuong Thien
    Vietnam National Institute of Medicinal Materials
  • Kim Ji Yeon
    Department of Surgery and Research Institute for Medicinal Sciences, Chungnam National University School of Medicine
  • Ahn Moon Sang
    Department of Surgery and Research Institute for Medicinal Sciences, Chungnam National University School of Medicine
  • Sul Ji Young
    Department of Surgery and Research Institute for Medicinal Sciences, Chungnam National University School of Medicine

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Overexpression/amplification of human epidermal growth factor receptor (HER)2/neu (erbB-2) oncogene plays a causal role in carcinogenesis and correlates with a poor clinical prognosis. However, little is known about HER2 in gastric cancer. In this study, we explored the pharmacological activities of natural triterpenoid corosolic acid (CRA) in HER2 signaling and its role in gastric cancer development and progression. In this study, CRA dramatically inhibited HER2 expression in a dose- and time-dependent manner, effectively inhibited cell proliferation, and induced G0/G1 arrest through the induction of p27kip1 and cyclin D1 down-regulation. CRA exposure enhanced apoptotic cell death, as confirmed by caspase-3 and poly (ADP-ribose) polymerase cleavage activities. CRA inhibited signaling pathways downstream of HER2, including phospho-proteins such as Akt and Erk. In addition, CRA combined with adriamycin and 5-fluorouracil enhanced this growth inhibition, but not with docetaxel and paclitaxel. These findings demonstrate that CRA suppresses HER2 expression, which in turn promotes cell cycle arrest and apoptotic cell death of gastric cancer cells, providing a rationale for future clinical trials of CRA in the treatment of HER2-positive gastric cancers.

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