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.

Alantolactone suppresses human osteosarcoma through the PI3K/AKT signaling pathway

“…accumulating evidence has indicated an important role of the Pi3K/aKT signaling pathway in osteosarcoma (11,34,35); Pi3K/aKT signaling modulates the proliferation, invasion, migration and apoptosis of osteosarcoma cell lines (36)(37)(38)(39)60). Previous studies revealed that alantolactone is a specific inhibitor in several diseases via the Pi3K/aKT signaling pathway (7,8).…”

“…Previous studies have reported that the Pi3K/aKT signaling pathway serves an important role in osteosarcoma (11,34,35); Pi3K/aKT modulates the proliferation, invasion, migration and apoptosis of osteosarcoma cell lines (36)(37)(38)(39). Thus, the effect of alT on the Pi3K/aKT signaling pathway was investigated to confirm whether it is the mechanism by which ALT affects osteosarcoma cells.…”

Increased expression of fatty acid synthase and acetyl-CoA carboxylase in the prefrontal cortex and cerebellum in the valproic acid model of autism

“…The FASN inhibitor C75 can repress the expression of FASN, ErbB1, ErbB2 and Akt, suggesting that FASN may participate in the ErbB/Akt pathway (24). The ErbB2 inhibitor lapatinib is able to suppress the activity of the ErbB2/PI3K/Akt/FASN pathway (25). Dysregulation of the PI3K/Akt pathway has been shown to have an association with autism (26); therefore, it is speculated that alterations of the ErbB2/PI3K/Akt/FASN signaling pathway may be involved in autism.…”

ErbB Receptors as Prognostic and Therapeutic Drug Targets in Bone and Soft Tissue Sarcomas

“…In human osteosarcoma, Lapatinib alters the malignant phenotype of cells via downregulation of the activity of the ErbB2-PI3K/AKT-FASN axis in vitro (103). A phase II trial on Lapatinib showed a modest antitumor activity in ErbB1-positive advance chordoma patients.…”