Metabolic targeting of pantothenate by medium chain fats in glioblastoma cells.

Ketogenic diets are commonly used for epilepsy therapy and are increasingly being considered in cancer treatment, where metabolic reprogramming triggered by glucose restriction and ketosis alters energy provision as the therapeutic mechanism. However, a recently developed medium chain triglyceride product, with a high decanoic acid (DA) to octanoic acid (OA) ratio (DA: OA) has enabled a much less restrictive diet and is clinically effective as an epilepsy treatment, yet no studies have explored the product in cancer models. Here we investigate metabolic mechanisms of DA, OA and DA: OA using a cellular glioblastoma model, focusing on changes in energy metabolism. We show, at a transcriptional level, that DA provides the dominant regulatory influence, enhancing transcription of fatty acid and amino acid metabolism pathways, while reducing cancer-associated glucose metabolism and kinase pathways. DA: OA treatment shared some of these effects, with little influence from OA. At a protein level, DA: OA treatment played the dominant role, regulating metabolic, cancer and signalling pathways, including a large network centred around albumin and protein kinase activities. Finally, at a metabolomic level, both DA and DA: OA treatment reduced vitamin B5 (pantothenate) levels, which is necessary for the synthesis of coenzyme A used in the activation of fatty acids for energy provision, suggesting a novel mechanism to reduce cellular energy provision in cancer. Importantly, these effects occur under high glucose conditions. Thus, we show that decanoic acid-rich treatments may regulate glioblastoma cell biology through targeted effects on glucose and fatty acid metabolism and kinase signalling and may trigger a potential reduction in pantothenate levels in glioblastoma cells, providing a potential novel therapeutic mechanism in cancer treatment.