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| Author(s): |
Fabiana Seguin
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Piracicaba, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Odontologia de Piracicaba |
| Defense date: | 2011-12-15 |
| Examining board members: |
Edgard Graner;
Vanessa Moraes Freitas;
Alan Roger Santos Silva;
Ana Paula de Souza;
Lays Martin Sobral
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| Advisor: | Edgard Graner |
| Abstract | |
Fatty acid synthase (FASN) is the anabolic enzyme with high expression and activity in several human malignancies, which is responsible for the endogenous synthesis of saturated fatty acids and consequently of the phospholipids present in cell membranes. Inhibition of FASN with orlistat (Xenical), an anti-obesity drug, is described as having anti-neoplastic properties in breast and prostate cancers as well as in melanoma. An anti-angiogenic role, has been attributed to this drug, since it inhibits the proliferation of endothelial cells and the neovascularization in ex vivo both assays. In recent studies performed by our group, it was demonstrated that the treatment of mice bearing intraperitoneal melanoma with orlistat reduced by 50% the number of metastases to mediastinal lymph nodes. In another study, also conducted by our group, we observed that the inhibition of FASN reduces the angiogenesis induced by experimental melanomas, since the density of blood vessels around tumors was significantly decreased by the treatment with orlistat. In the present work investigated the consequences of the treatment with FASN inhibitors the proliferation and apoptosis cultured endothelial cells. The expression of the VEGF family of growth factors were assessed by quantitative RT-PCR in both melanoma and squamous cell carcinoma cells. The results show that orlistat and cerulenin inhibit the viability and induce apoptosis and reduce the formation of blood vessels by RAEC cells in vitro. However, the same treatment does not reduce the viability and not reduce the formation of blood vessels by HUVEC cells in vitro. The inhibition of FASN in neoplastic cells SK-MEL-25 and SCC-9 increases the expression of mRNAs for VEGF and the conditioned medium by these cells with orlistat reduces the formation of blood vessels in vitro and proliferation of HUVEC cells. Together, the experiments show that FASN seems to be important for the survival of RAEC cells and FASN inhibition modulates the expression of VEGF isoforms (AU) | |