Abstract
Ketone bodies [beta-hydroxybutyrate (bHB) and acetoacetate] are mainly produced in the liver during prolonged fasting or starvation. bHB is a very efficient energy substrate for sustaining ATP production in peripheral tissues; importantly, its consumption is preferred over glucose. However, the majority of malignant cells, particularly cancer cells of neuroectodermal origin such as glioblastoma, are not able to use ketone bodies as a source of energy. Here, we report a novel observation that fenofibrate, a synthetic peroxisome proliferator-activated receptor alpha (PPARa) agonist, induces bHB production in melanoma and glioblastoma cells, as well as in neurospheres composed of non-transformed cells. Unexpectedly, this effect is not dependent on PPARa activity or its expression level. The fenofibrate-induced ketogenesis is accompanied by growth arrest and downregulation of transketolase, but the NADP/NADPH and GSH/GSSG ratios remain unaffected. Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic) therapeutic approaches against glioblastoma.
Highlights
Adaptation to limited nutritional resources due to a constantly changing environment is the most elementary challenge for organisms that are subjected to the pressures of natural selection
In this paper, we present a novel observation that malignant cells of neuroectodermal origin, namely melanoma and glioblastoma cells, are capable of efficient synthesis and release of bHB when treated with a synthetic peroxisome proliferator-activated receptor alpha (PPARa) agonist, fenofibrate
In order to further investigate the strong impact that fenofibrate has on the cellular metabolism and to distinguish the receptor dependent and independent effects, we performed the experiments on neoplastic cell lines with varying levels of PPARa expression
Summary
Adaptation to limited nutritional resources due to a constantly changing environment is the most elementary challenge for organisms that are subjected to the pressures of natural selection. Utilization of ketone bodies as a source of energy requires expression of enzymes involved in acetoacetate and bHB catabolism, such as succinyl-CoA:acetoacetate-CoA transferase (SCOT), known as 3-oxoacid-CoA transferase (OXCT1) (EC 2.8.3.5); 3-oxoacyl-CoA thiolase, known as acetyl-CoA actyltransferase (ACAT) (EC 2.3.1.9); and bHB dehydrogenase (EC 1.1.1.30) All of these enzymes are present in peripheral tissues at various levels; SCOT is absent in the liver to prevent a futile cycle of bHB synthesis and utilization [25]. The ability to synthesize ketone bodies is frequently lost during oncogenic transformation of colonic epithelia, where the c-Myc oncogene transcriptionally repressed transcription of the HMGCS2 gene in 90% of colon carcinoma samples tested [43] All these lines of evidence strongly suggest that ketogenesis is a process that is observed only under very particular physiological circumstances, which are absent in cancer cells. The induced ketogenesis seems to be independent of PPARa expression level or its activity in these cells
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