Inhibiting Delta-6 Desaturase Activity Suppresses Tumor Growth in Mice

Chengwei He,Chun Cai,Xiying Qu,Jianbo Wan,Lili Huang,Yan Gu,Keyuan Zhou,Rong Rong,Jing X Kang,Steven Y Qian

doi:10.1371/journal.pone.0047567

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.

Highlights

The identification of factors that modulate tumorigenesis is crucial for cancer prevention and treatment
To determine whether there is a difference in Delta-6 desaturase (D6D) activity between tumor and non-tumor tissues, we analyzed the activity of biomarkers of the D6D enzyme and expression levels in tumor and non-tumor tissues from B16 melanoma and Lewis lung cancer (LLC) tumors implanted in C57B6 mice
The results show that the tumor tissue content of arachidonic acid (AA) was 4 times greater for B16 melanoma (Figure 1A) and 2 times greater for LLC tumors (Figure 1B), compared to adjacent non-tumor tissues

Summary

Introduction

The identification of factors that modulate tumorigenesis is crucial for cancer prevention and treatment. Current research shows that targeting cancer metabolism or factors that modulate the tumor microenvironment may be promising venues for cancer therapy [3,4]. Arachidonic acid (AA), an omega-6 (n26) polyunsaturated fatty acid, is converted through three major pathways– the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 epoxygenase pathways–into bioactive lipid mediator eicosanoids, including prostaglandins (PGs), leukotrienes (LTs), and epoxyeicosatrienoids (EETs), respectively [5,6] (Figure S1). These metabolites have crucial roles in chronic inflammation and cancer [5,6,7]. AA-derived pro-inflammatory eicosanoids, PGE2 and LTB4 which are produced by tumor cells and their surrounding stromal cells, are key mediators in their crosstalk and can accelerate tumor growth and metastasis through several mechanisms [5], including: 1) directly activating their receptors on tumor cells to induce cell proliferation, survival, migration, and invasion through multiple signaling pathways in both autocrine and paracrine manners, 2)

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