Dietary Lipid, Palmitate, Alters Critical Metabolic Reprogramming Genes in Meningioma

The strong correlation between cancer and poor dietary habits such as high sugar and fat intake has been known for decades. However, only after the recent metabolomics revolution, we began to unravel how poor diet and metabolic reprogramming help cancer to adapt and thrive. Recently, aberrant fatty acid (FA) metabolism gained attention as a critical metabolic adaptation enabling cancer survival. Hence, FA targeting approaches emerged as therapeutic options for several cancers including breast cancer, prostate cancer and gliomas. In the present study, we investigated the effect of dietary lipid palmitate on metabolic reprogramming of meningiomas, the most common primary adult brain tumor. Similar to gliomas, meningiomas also show dysregulated FA metabolism which correlates with worse prognosis. Yet the underlying molecular pathways of this phenomena remains undiscovered to date. To tackle these pathways, we modeled meningioma pathology using well-established meningioma cell lines: IOMM-Lee, CH157-MN and AC599 each representing different molecular and histopathological characteristics of the disease. We exposed meningioma cell lines to varying doses of palmitate to determine their corresponding IC50 values. As a result of our dose response studies, we concluded extracellular palmitate exerts cytotoxic effect on all cell lines at high dose and long-term exposure. Effect of palmitate on cell viability is comparable within IOMM Lee, CH157-MN and AC599. Next, in order to delineate the effects of palmitate on gene expression we exposed cells to 200 uM palmitate for 24 hours and evaluated differential gene expression using QPCR assay. Among genes investigated, Aldehyde Oxidase1(AOX1) which encodes an adipogenic/xenobiotic enzyme showed a significant down regulation in malignant cell lines CH157-MN and IOMM- Lee, while it was slightly upregulated in benign cell line AC599. Our results align with the findings of others showing that AOX1 plays a role in a fatty acid metabolic reprogramming. Moreover, down regulation of AOX1 was positively correlated with tumor grade. This suggests that AOX1 downregulation can enable survival of meningiomas in challenging environments and foster tumorigenic behavior. Finally, our findings indicates that FA-AOX1 axis could be exploited for drug targeting studies for treatment of malignant meningiomas.