Sesamin regulates breast cancer through reprogramming of lipid metabolism

Metabolic reprogramming is one of the hallmarks of breast cancer (BC), involving elevated synthesis and uptake of lipids, for catering to increased energy demand of cancer cells and to suppress the host immune system. Besides promoting proliferation and survival of BC cells, lipid metabolism reprogramming (LMR) is associated with stemness and chemoresistance. Recently, lignans have been reported for their therapeutic potential against different cancers, including BC. Here, we explored the potential of lignans to target LMR pathways in BC through computational approach. Initially, 88 lignans having potential anticancer activities, underwent druglikeness and pharmacokinetics analysis, displaying promising pharmacokinetic properties, except for 13 molecules with violations. Molecular docking assessed the interaction of 88 lignans (NPACT) with therapeutic targets of LMR including 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), Sterol regulatory element-binding proteins 1 and 2 (SREBP1 and 2), Low-density lipoprotein receptor (LDLR), Acetyl-CoA Acetyltransferase 1 (ACAT1), ATP-binding cassette transporter (ABCA1), Liver X receptor α (LXRα), Apolipoprotein A1 (APOA1), Fatty Acid Synthase (FASN), Peroxisome proliferator-activated receptor gamma (PPARG), Stearoyl-CoA desaturase (SCD1), Acetyl-CoA carboxylase 1 and 2 (ACC1/ACACA, and ACC2/ACACB). In silico screening revealed sesamin (SE) as the best-identified hit that showed stable and consistent binding with all the selected targets of LMR. The stability of these complexes was validated by a 100 ns simulation run, and their binding free energy calculation was determined by MM-PBSA method. Interestingly, SE modulated the mRNA expression of genes involved in LMR in BC cell lines, MCF-7 and MDA-MB-231, thereby suggesting its potential as an inhibitor of LMR.