Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells.
Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells.
复制标题
DOI：
10.1016/j.redox.2017.01.016
复制
发表时间：
2017-04
期刊：
影响因子：
11.4
通讯作者：
Qian SY
中科院分区：
文献类型：
--
作者：
Yang X;Xu Y;Wang T;Shu D;Guo P;Miskimins K;Qian SY
我们最近报道了delta-5去饱和酶（一种将二homo-γ-亚麻酸，DGLA转化为下游ω-6花生四烯酸的关键酶）的敲低促进环加氧酶（COX）催化的DGLA过氧化反应产生抗癌副产物8-羟基辛酸。8-羟基辛酸可以作为组蛋白去乙酰化酶抑制剂对癌细胞（如结肠癌和胰腺癌）发挥生长抑制作用。由于组蛋白去乙酰化酶抑制剂已经被认为可以抑制癌细胞的迁移和侵袭，因此我们测试了敲低-5-去饱和酶和DGLA治疗是否也可以用来抑制结肠癌和胰腺癌细胞的迁移和侵袭。采用伤口愈合实验、transwell实验和western blot检测细胞迁移、侵袭及相关分子机制。在过度表达COX-2的癌细胞中，通过shRNA转染降低其δ -5去饱和酶，通过cox催化的DGLA过氧化作用，定量地形成8-羟基辛酸的阈值水平。我们的研究结果表明，敲低δ -5-去饱和酶并补充DGLA不仅能显著抑制细胞迁移，还能提高5-氟尿嘧啶和吉西他滨这两种目前分别用于治疗结肠癌和胰腺癌的一线化疗药物的疗效。这些观察结果的分子机制是8-羟基辛酸抑制组蛋白去乙酰化酶，导致肿瘤转移启动子如MMP-2和MMP-9下调，肿瘤转移抑制子如E-cadherin上调。我们首次证明了我们可以利用COX-2在癌症中普遍存在的过表达现象来抑制癌细胞的迁移和侵袭。随着COX-2癌症生物学范式的转变，我们的研究成果可能为我们提供一种新的癌症治疗策略。高水平的COX-2可用于抑制癌细胞的迁移和侵袭。8-羟基辛酸通过抑制HDAC抑制肿瘤的迁移和侵袭。D5D敲除和DGLA可提高化疗抑制肿瘤转移的效果。
We recently reported that knockdown of delta-5-desaturase (a key enzyme that converts dihomo-γ-linolenic acid, DGLA, to the downstream ω-6 arachidonic acid) promotes formation of an anti-cancer byproduct 8-hydroxyoctanoic acid from cyclooxygenase (COX)-catalyzed DGLA peroxidation. 8-hydroxyoctanoic acid can exert its growth inhibitory effect on cancer cells (e.g. colon and pancreatic cancer) by serving as a histone deacetylase inhibitor. Since histone deacetylase inhibitors have been well-known to suppress cancer cell migration and invasion, we thus tested whether knockdown of delta-5-desaturase and DGLA treatment could also be used to inhibit cancer migration and invasion of colon cancer and pancreatic cancer cells. Wound healing assay, transwell assay and western blot were used to assess cell migration and invasion as well as the associated molecular mechanisms. Formation of threshold level of 8-hydroxyoctanoic acid was quantified from COX-catalyzed DGLA peroxidation in the cancer cells that overexpress COX-2 and their delta-5-desaturases were knocked down by shRNA transfection. Our results showed that knockdown of delta-5-desaturase along with DGLA supplement not only significantly inhibited cell migration, but also improved the efficacies of 5-flurouracil and gemcitabine, two frontline chemotherapy drugs currently used in the treatment of colon and pancreatic cancer, respectively. The molecular mechanism behind these observations is that 8-hydroxyoctanoic acid inhibits histone deacetylase, resulting in downregulation of cancer metastasis promotors, e.g., MMP-2 and MMP-9 as well as upregulation of cancer metastasis suppressor, e.g. E-cadherin. For the first time, we demonstrated that we could take the advantage of the common phenomenon of COX-2 overexpression in cancers to inhibit cancer cell migration and invasion. With the shifting paradigm of COX-2 cancer biology, our research outcome may provide us a novel cancer treatment strategy. High level of COX-2 could be used to inhibit cancer cell migration and invasion. 8-hydroxyoctanoic acid suppresses cancer migration and invasion via inhibiting HDAC. D5D knockdown and DGLA improves efficacy of chemotherapy to inhibit cancer metastasis.
影响因子：
3.8
作者：
Kobayashi H;Uetake H;Higuchi T;Enomoto M;Sugihara K
通讯作者：
Sugihara K