Antiproliferative effects of γ-tocotrienol are associated with lipid raft disruption in HER2-positive human breast cancer cells
Antiproliferative effects of γ-tocotrienol are associated with lipid raft disruption in HER2-positive human breast cancer cells
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DOI：
10.1016/j.jnutbio.2015.09.018
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发表时间：
2016-01-01
影响因子：
5.6
通讯作者：
Sylvester, Paul W.
中科院分区：
文献类型：
--
作者：
Alawin, Osama A.;Ahmed, Rayan A.;Sylvester, Paul W.
很大比例的人乳腺癌的特征在于过度或异常的HER 2活性。脂筏是质膜内的特化微区，其是HER 2活化和信号转导所需的。由于γ-生育三烯酚的抗癌活性与HER 2信号传导的抑制相关，因此进行了研究以检查γ-生育三烯酚对HER 2阳性SKBR 3和BT 474人乳腺癌细胞中脂筏微结构域内HER 2活化的影响。用0-5 μ M γ-生育三烯酚处理诱导了5天培养期后癌细胞生长的显著剂量依赖性抑制，并且这些生长抑制作用与HER 2二聚化和磷酸化（活化）的减少相关。发现磷酸化的HER 2主要位于溶剂处理的对照组中质膜的脂筏微区中，而γ-生育三烯酚处理显著抑制该作用。质膜亚细胞组分的测定表明，γ-生育三烯酚也积累专门的脂筏微域内。羟丙基-β-环糊精（HP β CD）是一种破坏脂筏完整性的物质。单独急性暴露于3 mM HP β CD没有影响，而单独急性暴露于20 μ M γ-生育三烯酚24小时显着降低SKBR 3和BT 474细胞活力。然而，与这些药物的联合治疗大大降低了γ-生育三烯酚在脂筏微区的积累和细胞毒性。总之，这些发现表明，γ-生育三烯酚的抗癌作用与其在脂筏微结构域中的蓄积以及随后对SKBR 3和BT 474人乳腺癌细胞中HER 2二聚化和活化的干扰相关。(C)2015 Elsevier Inc. All rights reserved.
A large percentage of human breast cancers are characterized by excessive or aberrant HER2 activity. Lipid rafts are specialized microdomains within the plasma membrane that are required for HER2 activation and signal transduction. Since the anticancer activity of gamma-tocotrienol is associated with suppression in HER2 signaling, studies were conducted to examine the effects of gamma-tocotrienol on HER2 activation within the lipid raft microdomain in HER2-positive SKBR3 and BT474 human breast cancer cells. Treatment with 0-5 mu M gamma-tocotrienol induced a significant dose-dependent inhibition in cancer cell growth after a 5-day culture period, and these growth inhibitory effects were associated with a reduction in HER2 dimerization and phosphorylation (activation). Phosphorylated HER2 was found to be primarily located in the lipid raft microdomain of the plasma membrane in vehicle-treated control groups, whereas gamma-tocotrienol treatment significantly inhibited this effect. Assay of plasma membrane subcellular fractions showed that gamma-tocotrienol also accumulates exclusively within the lipid raft microdomain. Hydroxypropyl-beta-cyclodextrin (HP beta CD) is an agent that disrupts lipid raft integrity. Acute exposure to 3 mM HP beta CD alone had no effect, whereas an acute 24-h exposure to 20 mu M gamma-tocotrienol alone significantly decreased SKBR3 and BT474 cell viability. However, combined treatment with these agents greatly reduced gamma-tocotrienol accumulation in the lipid raft microdomain and cytotoxicity. In summary, these findings demonstrate that the anticancer effects of gamma-tocotrienol are associated with its accumulation in the lipid raft microdomain and subsequent interference with HER2 dimerization and activation in SKBR3 and BT474 human breast cancer cells. (C) 2015 Elsevier Inc. All rights reserved.