ABSTRACT
BACKGROUND: Fatty acid synthase (FASN) is overexpressed and associated with poor prognosis in several human cancers. Here, we investigate the effect of FASN inhibitors on the metastatic spread and angiogenesis in experimental melanomas and cultured melanoma cells. METHODS: The lung colonisation assay and cutaneous melanomas were performed by the inoculation of mouse melanoma B16-F10 cells in C57BL6 mice. Blood vessel endothelial cells (RAEC and HUVEC) were applied to determine cell proliferation, apoptosis, and the formation of capillary-like structures. Vascular endothelial growth factor A (VEGFA) expression was evaluated by quantitative RT-PCR and ELISA in B16-F10, human melanoma (SK-MEL-25), and human oral squamous carcinoma (SCC-9) cells. Conditioned media from these cancer cell lines were used to study the effects of FASN inhibitors on endothelial cells. RESULTS: B16-F10 melanoma-induced metastases and angiogenesis were significantly reduced in orlistat-treated mice. Fatty acid synthase inhibitors reduced the viability, proliferation, and the formation of capillary-like structures by RAEC cells, as well as the tumour cell-mediated formation of HUVEC capillary-like structures. Cerulenin and orlistat stimulated the production of total VEGFA in B16-F10, SK-MEL-25, and SCC-9 cells. Both drugs also enhanced VEGFA(121), (165), (189,) and (165b) in SK-MEL-25 and SCC-9 cells. CONCLUSION: FASN inhibitors reduce metastasis and tumour-induced angiogenesis in experimental melanomas, and differentially modulate VEGFA expression in B16-F10 cells.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Fatty Acid Synthases/antagonists & inhibitors , Lactones/pharmacology , Lung Neoplasms/prevention & control , Melanoma, Experimental/drug therapy , Melanoma/drug therapy , Neovascularization, Pathologic/prevention & control , Vascular Endothelial Growth Factor A/metabolism , Animals , Apoptosis/drug effects , Carcinoma, Squamous Cell/drug therapy , Cell Proliferation/drug effects , Cell Survival/drug effects , Enzyme-Linked Immunosorbent Assay , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lung Neoplasms/secondary , Melanoma/blood supply , Melanoma/secondary , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Mouth Neoplasms/drug therapy , Orlistat , RNA, Small Interfering , Reverse Transcriptase Polymerase Chain Reaction , Vascular Endothelial Growth Factor A/drug effectsSubject(s)
Carcinoma, Squamous Cell/pathology , Fibroblasts/pathology , Tongue Neoplasms/pathology , Actins/metabolism , Adult , Carcinoma, Squamous Cell/metabolism , Female , Humans , Immunohistochemistry , Male , Neoplasm Staging , Precancerous Conditions/pathology , Prognosis , Stromal Cells/pathology , Tongue/cytology , Tongue/pathology , Tongue Neoplasms/metabolismABSTRACT
Osteoporosis is commonly associated with estrogen deficiency. However, the mechanisms by which the lack of this hormone causes bone loss are poorly understood. The bone structure of the oral cavity seems to be affected by estrogen deficiency, since a delayed healing process after tooth extraction has been observed after ovariectomy in rats. The aim of this study was to describe the effect of the absence of estrogen on the expression and activity of matrix metalloproteinases (MMC)-2 and -9 and expression of types I and III collagens in the alveolar granulation tissue of young female rats after tooth extraction. Sixty-six, four-week-old female rats underwent bilateral ovariectomies (OVX) or sham operations. Three weeks later, both first and second mandibular molars were extracted and the animals were killed by cervical dislocation 3, 5, or 7 days after tooth extraction. The granulation tissues were collected from the extracted alveolar sockets and used for zymographic, Western blot, or reverse transcription polymerase chain reaction (RT-PCR) analysis. There was a gradual increase on the expression of all studied proteins as well as MMP-2 and -9 activities in the periods after surgery. In contrast, OVX animals showed a significant decrease in the gelatinolytic activities and expression of MMP-2 and -9 and types I and III collagens. The results presented here in suggest that the absence of estrogen may possibly contribute to the delayed alveolar wound healing by interfering with the extracellular matrix turnover.
