FADS2 function loss at the cancer hotspot 11q13 locus diverts lipid signaling precursor synthesis to unusual eicosanoid fatty acids

Abstract

Background: Genes coding for the fatty acid desaturases (FADS1, 2, 3) localized at the cancer genomic hotspot 11q13 locus are required for the biosynthesis of 20 carbon polyunsaturated fatty acids (PUFA) that are direct eicosanoid precursors. In several cancer cell lines, FADS2 encoded Δ6 and Δ8 desaturation is not functional.

Methodology/principal findings: Analyzing MCF7 cell fatty acids with detailed structural mass spectrometry, we show that in the absence of FADS2 activity, the FADS1 product Δ5-desaturase operates to produce 5,11,14-20∶3 and 5,11,14,17-20∶4. These PUFA are missing the 8-9 double bond of the eicosanoid signaling precursors arachidonic acid (5,8,11,14-20∶4) and eicosapentaenoic acid (5,8,11,14,17-20∶5). Heterologous expression of FADS2 restores Δ6 and Δ8-desaturase activity and normal eicosanoid precursor synthesis.

Conclusions/significance: The loss of FADS2-encoded activities in cancer cells shuts down normal PUFA biosynthesis, deleting the endogenous supply of eicosanoid and downstream docosanoid precursors, and replacing them with unusual butylene-interrupted fatty acids. If recapitulated in vivo, the normal eicosanoid and docosanoid cell signaling milieu would be depleted and altered due to reduction and substitution of normal substrates with unusual substrates, with unpredictable consequences for cellular communication.

Figure 1. GC results of transfected MCF7 cells with18∶2n-6 and18∶3n-3 fatty acids.

A: No product is seen in FADS1-transfected cells. B: FADS2 transfected cells Δ6-desaturate 18∶2n−6→18∶3n−6 (9,12–18∶2 → 6,9,12–18∶2) and 18∶3n–3→18∶4n−3 (9,12,15–18∶3 → 6,9,12,15–18∶4).

Figure 2. GC results of FADS2 transfected MCF7 cells with 20∶2n−6 (8,11–20∶2) and 20∶3n−3 (8,11,14–20∶3) fatty acids.

A: FADS1-transfected cells Δ5-desaturate 20∶2n−6→5,11,14–20∶3 and 20∶3n−3→5,11,14,17–20∶4. B: FADS2 transfected cells Δ8-desaturate 20∶2n−6→20∶3n−6 and 20∶3n−3→20∶4n−3.

Figure 3. n−6 LCPUFA pathway in MCF7 cells.

Δ6- and Δ8-desaturation steps are absent in MCF7, leading to Δ5-desaturation of 11,14–20∶2 to 5,11,14–20∶3 when FADS1 is functional. The analogous pathways for n–3 LCPUFA convert 11,14,17–20∶3→5,11,14,17–20∶4 (not shown). FADS2 is also believed to be involved in C22 LCPUFA biosynthesis (not shown).