Un nou inhibidor sintètic de la sintasa d’àcids grassos (FASN) amb efectes citotòxics

Abstract

Breast cancer affects more than 1.500.000 of women and it is responsible for more than 500.000 worldwide each year. Tumour cells have the ability to synthesize fatty acids de novo to supply the high demand of energy and synthesis of structures resulting from the high rates of proliferation. Thus, Fatty Acid Synthase (FASN), an enzyme of 270 KDa responsible of lypogenesis, is overexpressed and hyperactivated in most cancers, including breast cancer. The inhibition of FASN causes specific cytotoxicity to cancer cells. For this reason, the development of FASN inhibitors is an interesting strategy for cancer treatment. In this work, we studied a potentially FASN inhibitory molecule, the FASN Inhibitor X (FIX), and we analyzed its effects on breast cancer cells HER2+. We have evaluated its effects on cell proliferation, FASN expression and activity and on associated signalling pathways, such as PI3K/Akt and AMPK. The results obtained show that the compound presents antiproliferative properties and it inhibits FASN activity without modifying its expression. Regarding FIX effects of signalling pathways,it has been observed an inhibition of proteins involved in cell proliferation, as Akt or S6, parallel to an AMPK activation, a sensor protein of cell energy levels. AMPK is activated at drug concentrations in which Akt is inhibited. Akt inhibition concomitant to AMPK activation is also observed in other FASN inhibitors, consequently these two mechanisms might be related. However, the relationship between AMPK and Akt is not well described and further studies would be needed to confirm it. To sum up, FIX molecule has shown an ability to inhibit FASN activity and to block proliferation signaling pathways. Consequently it could represent a potential anticancer drug if these results were confirmed in other cell lines and animal models