Inhibiting delta-6 desaturase activity suppresses tumor growth in mice.
Inhibiting delta-6 desaturase activity suppresses tumor growth in mice.
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DOI：
10.1371/journal.pone.0047567
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kang JX
中科院分区：
文献类型：
--
作者：
He C;Qu X;Wan J;Rong R;Huang L;Cai C;Zhou K;Gu Y;Qian SY;Kang JX
最近的研究表明，肿瘤支持性微环境的特征是高水平的促炎和促血管生成类花生酸，这些类花生酸来源于omega-6（n−6）花生四烯酸（AA）。虽然产生这些n-6 AA类花生酸的代谢途径（考克斯、LOX和P450）已被靶向，但内源性AA产生在肿瘤发生中的作用仍未探索。δ-6去饱和酶（D 6D）是负责合成n-6 AA的限速酶，增加D 6D活性可导致n-6 AA产量增加。在这里，我们发现D 6D活性在黑色素瘤和肺肿瘤生长过程中上调，并且通过RNAi敲低或特异性D 6D抑制剂抑制D 6D活性，显著降低肿瘤生长。因此，AA和AA衍生的促肿瘤代谢物的含量显著降低。血管生成和炎症状态也减少。这些结果确定D 6D是肿瘤生长的关键因素，也是癌症治疗和预防的潜在靶点。
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.
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影响因子：
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