A Lipidomics-Based Approach to Study Fatostatin-Induced Toxicity

Abstract

Despite the well-known biological heterogeneity that exists between different types of cancer, they each undergo metabolic reprogramming to promote unregulated proliferation and tumor growth. This metabolic reprogramming involves the upregulation of processes that help the cell to meet increased bioenergetic and biosynthetic needs. One such process is fatty acid biosynthesis, which provides cells with thousands of diverse lipid species, each with unique functional roles for membrane structures or cellular signaling. The development of a targeted drug therapy to inhibit fatty acid biosynthesis could therefore have an impact on the treatment of many types of cancer. The small molecule fatostatin, which downregulates fatty acid biosynthesis through inhibition of a key transcription factor, has thus become the subject of many research investigations due to its potential as a widely effective cancer therapeutic agent. Through these studies, anti-tumor, anti-lipogenic, and anti-mitotic properties of fatostatin have been established. Despite wide interest and extensive research efforts, the mechanisms of fatostatin’s anti-cancer effects remain unclear. To investigate these effects, we used cell viability assays to examine the anti-proliferative effect of fatostatin on cancerous and non-cancerous cell lines, revealing different responses to treatment over time. To better understand the mechanisms responsible for these anti-cancer effects, we employed a global lipidomic analysis to investigate the lipidome during fatostatin treatment. This approach offers unbiased identification of lipid species that significantly change in abundance during fatostatin treatment, indicating that they are likely linked to fatostatin’s mechanism. Untargeted analysis has revealed the accumulation of unsaturated triacyglycerols and fatty acids and the depletion of acyl carnitines during fatostatin treatment. We have begun to investigate the mechanisms responsible for these regulation changes, providing new insight into fatostatin’s mode of action.