GD3 synthase overexpression sensitizes hepatocarcinoma cells to hypoxia and reduces tumor growth by suppressing the cSrc/NF-kappaB survival pathway.
GD3 synthase overexpression sensitizes hepatocarcinoma cells to hypoxia and reduces tumor growth by suppressing the cSrc/NF-kappaB survival pathway.
复制标题
DOI：
10.1371/journal.pone.0008059
复制
发表时间：
2009-11-26
期刊：
影响因子：
3.7
通讯作者：
Fernandez-Checa JC
中科院分区：
文献类型：
--
作者：
Lluis JM;Llacuna L;von Montfort C;Bárcena C;Enrich C;Morales A;Fernandez-Checa JC
低氧介导的HIF-1α稳定和NF-κB活化通过促进癌细胞存活、血管生成和肿瘤侵袭在肿瘤发生中起关键作用。神经节苷脂是生物膜不可或缺的组成部分，作为信号中间体的作用日益受到重视。特别地，神经节苷脂GD 3已被表征为通过促进细胞死亡信号传导和抑制存活途径的促凋亡脂质效应物。因此，我们的目的是分析GD 3在肝癌细胞缺氧敏感性和体内肿瘤生长中的作用。我们产生并表征了稳定表达GD 3合酶（Hep 3B-GD 3）的人肝癌细胞系，其催化从GM 3合成GD 3。尽管GD 3水平增加（2-3倍），但与常氧下的野生型Hep 3B细胞相比，在Hep 3B-GD 3细胞中未观察到细胞形态或生长的显著变化。然而，暴露于缺氧（2%O2）的Hep 3B-GD 3细胞增强活性氧（ROS）的产生，导致细胞存活率下降，在暴露于增加剂量的外源性GD 3的Hep 3B细胞中观察到类似的结果。另外，缺氧可诱导Hep 3 B细胞c-Src酪氨酸磷酸化，NF-κB B活化，Mn-SOD表达增加，而Hep 3 B-GD 3细胞则无此变化。此外，MnTBAP，一种具有主要SOD模拟活性的抗氧化剂，减少ROS的产生，保护Hep 3B-GD 3细胞免于缺氧诱导的死亡。最后，与Hep 3B肿瘤异种移植物相比，在Hep 3B-GD 3中观察到较低的肿瘤生长、较高的细胞死亡和降低的Mn-SOD表达。这些发现强调了GD 3通过使c-Src/NF-κB存活途径失效而在缺氧易感性中的作用，从而导致Mn-SOD表达降低，这可能与肝细胞癌治疗相关。
Hypoxia-mediated HIF-1α stabilization and NF-κB activation play a key role in carcinogenesis by fostering cancer cell survival, angiogenesis and tumor invasion. Gangliosides are integral components of biological membranes with an increasingly recognized role as signaling intermediates. In particular, ganglioside GD3 has been characterized as a proapoptotic lipid effector by promoting cell death signaling and suppression of survival pathways. Thus, our aim was to analyze the role of GD3 in hypoxia susceptibility of hepatocarcinoma cells and in vivo tumor growth. We generated and characterized a human hepatocarcinoma cell line stably expressing GD3 synthase (Hep3B-GD3), which catalyzes the synthesis of GD3 from GM3. Despite increased GD3 levels (2–3 fold), no significant changes in cell morphology or growth were observed in Hep3B-GD3 cells compared to wild type Hep3B cells under normoxia. However, exposure of Hep3B-GD3 cells to hypoxia (2% O2) enhanced reactive oxygen species (ROS) generation, resulting in decreased cell survival, with similar findings observed in Hep3B cells exposed to increasing doses of exogenous GD3. In addition, hypoxia-induced c-Src phosphorylation at tyrosine residues, NF-κB activation and subsequent expression of Mn-SOD were observed in Hep3B cells but not in Hep3B-GD3 cells. Moreover, MnTBAP, an antioxidant with predominant SOD mimetic activity, reduced ROS generation, protecting Hep3B-GD3 cells from hypoxia-induced death. Finally, lower tumor growth, higher cell death and reduced Mn-SOD expression were observed in Hep3B-GD3 compared to Hep3B tumor xenografts. These findings underscore a role for GD3 in hypoxia susceptibility by disabling the c-Src/NF-κB survival pathway resulting in lower Mn-SOD expression, which may be of relevance in hepatocellular carcinoma therapy.
登录
查看更多内容
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
4.7
作者：
Birklé, S;Ren, SL;Yu, RK
通讯作者：
Yu, RK
影响因子：
8
作者：
Morales, A.;Paris, R.;Fernandez-Checa, J. C.
通讯作者：
Fernandez-Checa, J. C.
影响因子：
3.5
作者：
Colell, A;García-Ruiz, C;Fernández-Checa, JC
通讯作者：
Fernández-Checa, JC
影响因子：
4.8
作者：
Moon, Sung-Kwon;Kang, Sung-Koo;Kim, Cheorl-Ho
通讯作者：
Kim, Cheorl-Ho