Fatty acid synthase inhibitor cerulenin attenuates glioblastoma progression by reducing EMT and stemness phenotypes, inducing oxidative and ER stress response, and targeting PI3K/AKT/NF-κB axis

Abstract

Targeting cellular metabolism is becoming a critical approach for stopping cancer progression. Limited information is available regarding the effects of inhibiting the lipogenic enzyme fatty acid synthase (FASN) in glioblastoma (GB) cells (grade-IV-astrocytoma), which have high invasion and low response to standard treatments. Herein, we used cerulenin (CER) to inhibit FASN. CER treatments (3.6 mu g/mL/48 h and 5.55 mu g/mL/48 h indicate IC20 and IC50 values, respectively) led to a dose- and time-dependent decrease in the viability of the U-87MG human GB cells. A significant decrease was detected in the levels of fatty acids, including palmitic acid, determined by GS-MS analysis. FASN inhibition attenuated cell motility, 2D and 3D-clonogenic survival, and cell differentiation characteristics (related markers of epithelial-mesenchymal transition/EMT and stemness). Moreover, treatments caused mitochondrial membrane potential (MMP) collapse and increased intracellular reactive oxygen species (ROS) levels. Protein aggregates and ER stress in the cells also increased. Remarkably, despite increased Hsp70 and p-HSF1 levels against induced cellular stress, CER promoted markedly autophagy and apoptosis. The network pharmacology approach revealed that protein and lipid kinases are crucial targets in cell signaling, and PI3K, AKT, and NF-kappa B levels were confirmed by immunoblotting. The results demonstrated for the first time that inhibiting FA production and FASN function induces cell death through ROS generation and ER stress while simultaneously reducing the motility and aggressiveness of U-87MG human glioblastoma cells by attenuating EMT and stemness phenotypes. Therefore, blocking lipid metabolism using CER may be considered as a good candidate for GB therapeutic option.