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.
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 G(0)/G(1) arrest through the induction of p27(kip1) and cyclin D(1) 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.
Regional Cancer Institute, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea.
Myung Sun
MS
Lee
Eun Young
EY
Cha
Phuong Thien
PT
Thuong
Ji Yeon
JY
Kim
Moon Sang
MS
Ahn
Ji Young
JY
Sul
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D018734:Genes, erbB-2; D006801:Humans; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy*; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D053148:Caspase 3; D010936:Plant Extracts; D011065:Poly(ADP-ribose) Polymerases; D018719:Erb-b2 Receptor Tyrosine Kinases; D014315:Triterpenes; C113861:corosolic acid