Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

Abstract

Malignant gliomas are the most common adult brain cancers. In spite of aggressive treatment, recurrence occurs in the great majority of patients and is invariably fatal. Polyunsaturated fatty acids are abundant in brain, particularly ω-6 arachidonic acid (AA) and ω-3 docosahexaenoic acid (DHA). Although the levels of ω-6 and ω-3 polyunsaturated fatty acids are tightly regulated in brain, the ω-6:ω-3 ratio is dramatically increased in malignant glioma, suggesting deregulation of fundamental lipid homeostasis in brain tumor tissue. The migratory properties of malignant glioma cells can be modified by altering the ratio of AA:DHA in growth medium, with increased migration observed in AA-rich medium. This fatty acid-dependent effect on cell migration is dependent on expression of the brain fatty acid binding protein (FABP7) previously shown to bind DHA and AA. Increased levels of enzymes involved in eicosanoid production in FABP7-positive malignant glioma cells suggest that FABP7 is an important modulator of AA metabolism. We provide evidence that increased production of eicosanoids in FABP7-positive malignant glioma growing in an AA-rich environment contributes to tumor infiltration in the brain. We discuss pathways and molecules that may underlie FABP7/AA-mediated promotion of cell migration and FABP7/DHA-mediated inhibition of cell migration in malignant glioma.

Keywords: AA; ALA; AP; Activator Protein; Arachidonic acid; Astrocytoma; COX; CYP; DGLA; DHA; Docosahexaenoic acid; EPA; Eicosanoids; FABP7 (B-FABP); Fatty acid binding protein; GFAP; GLA; LA; LDL; LOX; Lipid metabolism; MAPK; Malignant glioma; NFI; Nuclear Factor I; PG; PLA(2); PPAR; PPAR response element; PPRE; PUFA; VLDL; arachidonic acid; brain fatty acid binding protein; cis-linoleic acid; cyclooxygenases; cytochrome P450; dihomo-gammalinolenic acid; docosahexaenoic acid; eicosapentaenoic acid; gamma-linolenic acid; glial fibrillary acidic protein; lipoxygenase; low density lipoprotein; mitogen-activated protein kinase; peroxisome proliferator-activated receptor; phospholipase A(2); polyunsaturated fatty acid; prostaglandin; very low density lipoprotein; α-linolenic acid.

Fig. 1

Outline of the conversion of linoleic acid and α-linolenic acid into arachidonic acid and docosahexaenoic acid, respectively by a combination of desaturases and elongases. Note that conversions of linoleic acid to gamma-linolenic acid, dihomo-gammalinolenic acid and α-linolenic acid to eicosapentaenoic acid are not shown.

Fig. 2

Diagrammatic representation of the balance between ω-3 and ω-6 fatty acids in normal brain and the deregulation of this balance in malignant glioma. A tightly controlled AA:DHA ratio is maintained in normal brain, with ω-3 deficiency and ω-6 deficiency resulting in enhanced AA/decreased DHA metabolism and enhanced DHA/decreased AA metabolism, respectively. This ratio is deregulated in malignant glioma tumors, with decreased DHA content and increased linoleic acid resulting in a significantly decreased ω-3:ω-6 ratio.

Fig. 3

Diagram depicting the role of FABP7 in the intracellular trafficking of fatty acids. Fatty acids AA or DHA are cleaved from membrane phospholipids depending on which PLA₂ isoform is activated. Upon release, AA or DHA binds to FABP7 which then translocates the fatty acid either to the nucleus, where it activates PPARs (for DHA) or to the endoplasmic reticulum for fatty acid metabolism (for AA).

Fig. 4

Diagrammatic representation of pathways that may be involved in FABP7-induced malignant glioma cell migration. Pro-migratory and anti-migratory pathways controlled through AA-FABP7 and DHA-FABP7, respectively, are indicated. ⁺ PPARβ/δ enhances COX-2 activity whereas PPARγ down-regulates COX-2.