Glioblastoma (GB) is the most common primary malignant brain tumor with a dismal median survival of 1.5 years. To address the need for novel therapeutics for the treatment of GB, investigations into high fat, low carbohydrate ketogenic diets (KD) have been explored as potential adjuvant therapeutic modalities. Preclinical studies of the KD in a mouse model of malignant glioma demonstrated that the KD extended median survival when used alone and substantially potentiated both radiotherapy and chemotherapy. However, the underlying mechanisms by which the KD exerts its therapeutic benefits remain poorly understood. A key result of the KD is the production of the ketone bodies β-hydroxybutyrate (βHB), acetoacetate, and acetone. Of these, BHB is the most prevalent ketone body produced. In order to elucidate the underlying molecular mechanisms of the KD, we have examined the interactions between BHB and the mouse glioma cell line GL261-Luc2. Previously, we demonstrated the ability of βHB to recapitulate the in vivo effects of the KD in tumor cells in an in vitro model. In the present study, we demonstrate that the ketone βHB is able to significantly down regulate the master transcription factor c-Myc, which is intimately involved in cell cycle progression, apoptosis, proliferation, DNA damage and repair, and metabolism. Overexpression of c-Myc is tied to a variety of human malignancies. In GB, upregulation of c-Myc signaling has been connected to an increase in tumor glucose metabolism. Furthermore, downregulating c-Myc expression has been demonstrated to confer sensitivity to tumors. We show that doses of both 5mM and 10mM βHB significantly reduced the expression of c-Myc in the GL261-Luc2 cell line when evaluated by both immunocytochemistry and western blot. Downregulation of c-Myc may, in part, be a mechanism by which βHB and thus the KD exert their radiosensitizing and antiproliferative effects on tumors. We intend to further investigate the role of c-Myc in the KD by investigating downstream targets of c-Myc as well as potential regulators of c-Myc transcription that are affected by BHB.

Citation Format: Alex P. Rossi, Helena B. Silva-Nichols, Eric C. Woolf, Adrienne C. Scheck. The ketone body β-hydroxybutyrate down regulates c-Myc signaling in a malignant glioma model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1022.