Lipid metabolism emerges as a promising target for malignant glioma therapy

Abstract

Malignant gliomas are one of the most treatment-refractory cancers. Development of resistance to chemo- and radio-therapies contributes to these tumors' aggressive phenotypes. Elevated lipid levels in gliomas have been reported for the last 50 years. However, the molecular mechanisms of how tumor tissues obtain lipids and utilize them are not well understood. Recently, the oncogenic signaling EGFR/PI3K/Akt pathway has been shown to enhance lipid synthesis and uptake by upregulating SREBP-1, a master transcriptional factor, to control lipid metabolism. This article discusses the analytical chemistry results of lipid components in glioma tissues from different research groups. The molecular mechanisms that link oncogenes with lipid programming, and identification of the key molecular targets and development of effective drugs to inhibit lipid metabolism in malignant gliomas will be discussed.

Figure 1.. Regulation of lipid metabolism in glioblastoma and the therapeutic drug targets.

Receptor tyrosine kinase/PI3K/Akt signaling via upregulation of SREBP-1 promotes fatty acid synthesis and cholesterol uptake. ACC and FAS are direct downstream genes of SREBP-1 and key molecules in the regulation of de novo fatty acid synthesis. LDLR is upregulated by SREBP-1 to promote cholesterol uptake. Activation of LXR stimulates ABCA1 expression and promotes cholesterol efflux; it also reduces LDLR levels via upregulating Idol, a ubiquitin ligase E3. The light red boxes designate the molecules upregulated in glioblastoma (GBM) and could be potential therapeutic targets in GBM. The light blue boxes signify the molecules that negatively regulate GBM growth. Fatostatin is a SREBP-1 inhibitor; GW3965 is a LXR synthetic agonist; HMG-CoA R is a key enzyme in the pathway of de novo cholesterol synthesis; and statin is a HMG-CoA R inhibitor. HMG-CoA R: HMG-CoA reductase; LDLR: Low-density lipoprotein receptor; RTK: Receptor tyrosine kinase.