ET-65THE KETOGENIC DIET REDUCES CARBONIC ANHYDRASE 9 AND ALTERS THE EXPRESSION OF PROTEINS INVOLVED WITH GLIOMA GROWTH AND PROGRESSION IN HYPOXIC CONDITIONS

摘要

Patients with malignant gliomas have a median survival of approximately 15 months following diagnosis, regardless of currently available treatments which include surgery, radiation and chemotherapy. Improvement in the survival of these patients requires the design of new therapeutic modalities that take advantage of common phenotypes. One such phenotype is metabolic dysregulation - a hallmark of cancer cells. It has been postulated that one approach to treating gliomas may be by metabolic alteration such as that which occurs through the use of the ketogenic diet (KD). The KD is high-fat, low-carbohydrate diet that induces ketosis and has been utilized for the non-pharmacologic treatment of refractory epilepsy. We and others have shown that this diet enhances survival and potentiates standard therapy in mouse models of glioma, yet the anti-tumor mechanisms are not fully understood. We have previously shown that the KD reduces peritumoral edema and tumor vasculature in a mouse model of glioma. We now show that tumors from animals fed the KD show reduced expression of the hypoxia marker carbonic anhydrase 9 (CA9) when compared to animals fed a standard rodent diet (SD). Protein analyses showed that the KD alters the expression of the tight junction protein zona occludens 1 (ZO-1), and the membrane water channel aquaporin-4 (AQPN4), which are regulated by tumor hypoxia and have been implicated in peritumoral edema. We also see a reduction in phosphorylated NF-κB which may result in reduced transcription of hypoxia-related genes. Further analysis showed that the KD reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2), which plays a key role in hypoxia-induced angiogenesis. Taken together our data offers insight into the anti-edema and anti-angiogenic mechanisms underlying the KD. A greater understanding of the effects of the KD as an adjuvant therapy will allow for a more rational approach to its clinical use.