The Ketogenic Diet Alters The Expression Of Micrornas That Play Key Roles In Tumor Development

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Glioblastoma multiforme (GBM) is the most common, and most aggressive, primary brain tumour in adults. Despite advances in surgical techniques and improvements in radiotherapy and chemotherapy protocols, the prognosis for patients with these tumors is extremely poor, with a median survival of 14 months in patients receiving maximal aggressive treatment. Although several targeted therapies have been tried in GBM, these have proved to be ineffective, with no targeted agent showing an improvement in overall survival. These dismal facts highlight the need for new therapeutic approaches. One strategy is to take advantage of the metabolic dysregulation of tumor cells and their high dependence on glucose for survival using dietary measures. This approach would target the tumor as a whole and help to overcome the problems associated with tumour heterogeneity. One such approach is the ketogenic diet, (KD). This high fat, low carbohydrate diet has been used clinically for the management of refractory paediatric epilepsy and has been shown to extend survival in a number of animal models of glioma. Furthermore, studies using the GL261-luc2 syngeneic intracranial model of malignant glioma also highlighted the ability of the KD to potentiate the effects of chemotherapy and radiotherapy. However, the mechanisms underlying these responses are poorly understood. MicroRNAs (miRs) are small noncoding single-stranded RNAs that are capable of altering mRNA expression of target genes and hence have crucial roles in a diverse array of biological processes. To investigate changes in the expression of miRs during the KD, we profiled brain tumors from mice fed either a KD or standard diet for differential miR expression using the miScript miRNA PCR Array Mouse Brain Cancer (Qiagen Ltd., Manchester, UK). We observed that miRs with an oncogenic potential were generally downregulated whereas those with a tumor suppressor function were upregulated in tumors from mice fed KD compared to tumors from mice fed SD. Upregulation of miR 296-5p is of particular interest, since its target, Pin 1, a Ser/Thr-Pro cis/trans isomerase, is a regulator of cell metabolism through its interaction with glycolytic enzymes for the Warburg effect. Furthermore, miR 296-5p has been implicated in DNA damaging chemotherapy resistance in breast and lung cancer cell lines. Taken together our results suggest that the KD could inhibit tumor growth and contribute to therapy sensitivity through differential expression of miRs. Citation Format: Julia Pazmandi, Kevin S. O'Neill, Adrienne C. Scheck, Peter W. Szlosarek, Eric C. Woolf, Kenneth S. Brooks, Nelofer Syed. The ketogenic diet alters the expression of microRNAs that play key roles in tumor development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 240. doi:10.1158/1538-7445.AM2015-240