Rossato 2014 PLoS One

[[Has title::Rossato FA, Zecchin KG, La Guardia PG, Ortega RM, Alberici LC, Costa RA, Catharino RR, Graner E, Castilho RF, Vercesi AE (2014) Fatty acid synthase inhibitors induce apoptosis in non-tumorigenic Melan-A cells associated with inhibition of mitochondrial respiration. PLoS One 9:e101060.]]

» [[Has info::PMID: 24964211]]

Was written by::Rossato FA, Was written by::Zecchin KG, Was written by::La Guardia PG, Was written by::Ortega RM, Was written by::Alberici LC, Was written by::Costa RA, Was written by::Catharino RR, Was written by::Graner E, Was written by::Castilho RF, Was written by::Vercesi AE (Was published in year::2014) Was published in journal::PLoS One

Abstract: [[has abstract::The metabolic enzyme fatty acid synthase (FASN) is responsible for the endogenous synthesis of palmitate, a saturated long-chain fatty acid. In contrast to most normal tissues, a variety of human cancers overexpress FASN. One such cancer is cutaneous melanoma, in which the level of FASN expression is associated with tumor invasion and poor prognosis. We previously reported that two FASN inhibitors, cerulenin and orlistat, induce apoptosis in B16-F10 mouse melanoma cells via the intrinsic apoptosis pathway. Here, we investigated the effects of these inhibitors on non-tumorigenic melan-a cells. Cerulenin and orlistat treatments were found to induce apoptosis and decrease cell proliferation, in addition to inducing the release of mitochondrial cytochrome c and activating caspases-9 and -3. Transfection with FASN siRNA did not result in apoptosis. Mass spectrometry analysis demonstrated that treatment with the FASN inhibitors did not alter either the mitochondrial free fatty acid content or composition. This result suggests that cerulenin- and orlistat-induced apoptosis events are independent of FASN inhibition. Analysis of the energy-linked functions of melan-a mitochondria demonstrated the inhibition of respiration, followed by a significant decrease in mitochondrial membrane potential (ΔΨm) and the stimulation of superoxide anion generation. The inhibition of NADH-linked substrate oxidation was approximately 40% and 61% for cerulenin and orlistat treatments, respectively, and the inhibition of succinate oxidation was approximately 46% and 52%, respectively. In contrast, no significant inhibition occurred when respiration was supported by the complex IV substrate N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD). The protection conferred by the free radical scavenger N-acetyl-cysteine indicates that the FASN inhibitors induced apoptosis through an oxidative stress-associated mechanism. In combination, the present results demonstrate that cerulenin and orlistat induce apoptosis in non-tumorigenic cells via mitochondrial dysfunction, independent of FASN inhibition.]]

• O2k-Network Lab: Was published by MiPNetLab::BR Campinas Vercesi AE

Labels: MiParea: MiP area::Respiration  Pathology: Diseases::Cancer  Stress:Injury and adaptation::Cell death  Organism: Organism::Mouse  Tissue;cell: tissue and cell::Endothelial;epithelial;mesothelial cell  Preparation: Preparation::Intact cells, Preparation::Permeabilized cells 

Coupling state: Coupling states::LEAK, Coupling states::OXPHOS, Coupling states::ETS  Pathway: Pathways::N, Pathways::S, Pathways::CIV, Pathways::NS  HRR: Instrument and method::Oxygraph-2k