title: Lapatinib alters the malignant phenotype of osteosarcoma cells via downregulation of the activity of the HER2-PI3K/AKT-FASN axis in vitro.
abstract: Lapatinib, an inhibitor of human epidermal growth factor receptor 2 (HER2) phosphorylation, has been reported to inhibit several types of tumors such as HER2-overexpressing breast cancer. However, the effect of lapatinib on the malignant phenotype of human osteosarcoma (OS) cells and the potential molecular mechanisms remain unclear. To elucidate the effect of lapatinib on OS, two OS cell lines, U2-OS and MG-63, were utilized in the present study. Various concentrations of lapatinib were used to treat OS cells for different time durations. Cell proliferation was evaluated by MTT and colony formation assays. Flow cytometry (FCM) was used to evaluate cell apoptosis. Wound healing and Transwell invasion assays were performed to examine the migratory and invasive abilities of the cells. To investigate the possible molecular mechanisms involved, the expression of p-HER2, phosphatidylinositol 3-kinase (PI3K), p-AKT, AKT and fatty acid synthase (FASN) protein was detected by western blotting. MTT assays showed that lapatinib inhibited the proliferation of U2-OS and MG-63 cells in a dose- and time-dependent manner, and the rate of colony formation of the lapatinib-treated cells was significantly lower when compared to those cells not treated with lapatinib in both cell lines. FCM assay revealed a significantly higher apoptotic rate in the lapatinib-treated OS cells. Wound healing and Transwell invasion assays revealed that the migratory and invasive abilities of OS cells were significantly inhibited by lapatinib (P<0.05). Western blotting showed that lapatinib suppressed the activity of HER2-PI3K/AKT-FASN in U2-OS and MG-63 cells in vitro. These results suggest that lapatinib may alter the malignant phenotype of OS cells via downregulation of the activity of the HER2-PI3K/AKT-FASN signaling pathway in vitro. Thus, lapatinib may be an effective chemotherapeutic agent for the treatment of osteosarcoma.
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Long
authors.forename: Guo-Mei
authors.initials: GM
authors.lastname: Zhang
authors.forename: Ai-Fen
authors.initials: AF
authors.lastname: Peng
authors.forename: Qing-Feng
authors.initials: QF
authors.lastname: Luo
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Hui-Cai
authors.initials: HC
authors.lastname: Wen
authors.forename: Rong-Ping
authors.initials: RP
authors.lastname: Zhou
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054890:Fatty Acid Synthase, Type I / Q000096:biosynthesis; D006801:Humans; D000077341:Lapatinib; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D054890:Fatty Acid Synthase, Type I; D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C518729:FASN protein, human; C508053:ERBB2 protein, human