Inhibiting Delta-6 Desaturase Activity Suppresses Tumor Growth in Mice

Abstract

Recent studies have shown that a tumor-supportive microenvironment is characterized by high levels of pro-inflammatory and pro-angiogenic eicosanoids derived from omega-6 (n−6) arachidonic acid (AA). Although the metabolic pathways (COX, LOX, and P450) that generate these n−6 AA eicosanoids have been targeted, the role of endogenous AA production in tumorigenesis remains unexplored. Delta-6 desaturase (D6D) is the rate-limiting enzyme responsible for the synthesis of n−6 AA and increased D6D activity can lead to enhanced n−6 AA production. Here, we show that D6D activity is upregulated during melanoma and lung tumor growth and that suppressing D6D activity, either by RNAi knockdown or a specific D6D inhibitor, dramatically reduces tumor growth. Accordingly, the content of AA and AA-derived tumor-promoting metabolites is significantly decreased. Angiogenesis and inflammatory status are also reduced. These results identify D6D as a key factor for tumor growth and as a potential target for cancer therapy and prevention.

Meta-Analysis of Long-Chain Omega-3 Polyunsaturated Fatty Acids (LCω-3PUFA) and Prostate Cancer

“…Chua et al (17) suggested that modifications in the androgen milieu from dietary fat intake may contribute to PC, and that the positive association observed for high-grade tumors may be due to a biochemical process in the prostate tissue. He et al (60) and Azordegan et al (61) both provide evidence that carcinogenesis (breast, lung) itself alters tissue fatty acid metabolism (e.g., increases in the activity of delta-6-desaturase). This could increase tissue (and possibly plasma) levels of LCv3PUFAs.…”

Heating of vegetable oils influences the activity of enzymes participating in arachidonic acid formation in Wistar rats

“…One of the factors that significantly affects desaturase activity is the kind and the composition of the supplied diet [2,[4][5][6][7][8][9]. Many studies showed the influence of low-fat diet, high-fat diet, and PUFA-enriched diet on the activity of Δ 6 -desaturase (D6D) [6,10]. The other inhibitors of this enzyme are fatty acids in the trans configuration, zinc, calcium, vitamin B 12 , and folic acid [3,[11][12][13].…”

Endogenous Production of Long-Chain Polyunsaturated Fatty Acids and Metabolic Disease Risk

“…He at al. found that reducing D6D activity through either RNAi knockdown or a selective D6D inhibitor reduced production of PGD 2 , PGE 2 , 12-HETE and 15-HETE by up to 80-95% in B16 melanoma cell lines [49]. They found a similar but lower reduction in these ARA-derived eicosanoids in LLC lung cancer cell lines.…”