Abstract 3230: Fenofibrate-mediated energy crisis and apoptotic cell death of glioblastoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Glioblastomas are one of the most aggressive brain tumors which are characterized by rapid cell growth, infiltration of the Central Nervous System (CNS), and resistance to all known anticancer regiments. Therefore, the development of new more effective therapies against Glioblastoma is the major challenge for modern medicine. Fenofibrate, a drug widely utilized to lower lipid concentration in the blood, is one of the very promising anti-cancer treatments with low systemic toxicity. This potent agonist of PPARδ is thought to shift energy metabolism from glycolysis to fatty acid α-oxidation and, therefore, it may be toxic to glycolysis -dependent brain tumor cells (Warburg effect). While the toxicity to cancer cells appears to be clear, the precise mechanism/s of fenofibrate action against brain tumors seems to be much more complex and remains to be elucidated. To understand metabolic basis of the anti-cancer action of fenofibrate, we have analyzed extracellular acidification (ECAR) and oxygen consumption (OCR) using XF 24 Extracellular Flux Analyzer (Seahorse Bioscience), mitochondrial membrane potential as well as ATP level in different glioblastoma cell lines (LN229, U87MG, T98G). Surprisingly, we found that basal oxygen consumption (OCR) decreased significantly in Glioblastoma cells pretreated with fenofibrate, and the addition of metabolic toxins did not change their metabolic profile. Decreased oxygen consumption was due to the direct interaction of fenofibrate with complex I, a protein involved in the mitochondrial electron transport chain. We additionally found that, in parallel to the metabolic changes, fenofibrate triggers cell cycle arrest followed by apoptosis. The mechanisms involve a PPARδ-mediated effect, which leads to the energy crisis and apoptosis, as well as a PPARδ-independent pathway which results in FOXO3a nuclear translocation and activation of the proapoptotic protein Bim. Overall our data strongly support an anticancer action of fenofibrate by shifting the glycolitic-dependent cell metabolism to fatty acids α-oxidation with subsequent energy crisis and apoptotic cell death. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3230. doi:1538-7445.AM2012-3230