γ-Tocotrienol-induced disruption of lipid rafts in human breast cancer cells is associated with a reduction in exosome heregulin content
γ-Tocotrienol-induced disruption of lipid rafts in human breast cancer cells is associated with a reduction in exosome heregulin content
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DOI：
10.1016/j.jnutbio.2017.06.013
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发表时间：
2017-10-01
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.
heregulin是一种激活HER 3和HER 4受体的有效配体，其过表达在乳腺癌患者化疗耐药性的发展中起着重要作用。从癌细胞释放的外泌体是源自脂筏向外出芽的小囊泡，其携带各种促有丝分裂蛋白，然后以自分泌/旁分泌方式局部作用以刺激癌细胞生长。由于γ-生育三烯酚的抗癌活性已显示部分通过破坏脂筏介导，因此进行研究以确定γ-生育三烯酚对外泌体促有丝分裂生物效能的影响。发现从培养的T47 D乳腺癌细胞的培养基中分离的外泌体以剂量依赖性方式刺激T47 D细胞生长。这些生长刺激作用是由于外泌体中含有高水平的调蛋白，其作用是刺激HER 3和HER 4活化、异源二聚化和促有丝分裂信号传导。暴露于5 μ M γ-生育三烯酚导致选择性积累和破坏的完整性的脂筏微结构域和相应的减少外泌体heregulin含量和促有丝分裂的生物效能。这些发现提供了强有力的证据，表明γ-生育三烯酚的抗癌作用至少部分是通过直接破坏HER二聚化和脂筏内的信号传导以及间接通过减少外泌体调蛋白含量和随后的自分泌/旁分泌促有丝分裂刺激来介导的。(C)2017爱思唯尔公司All rights reserved.
Overexpression of heregulin, a potent ligand that activates HER3 and HER4 receptors, plays a significant role in the development of chemotherapy resistance in breast cancer patients. Exosomes released from cancer cells are small vesicles originating from the outward budding of lipid rafts that carry various mitogenic proteins that then act locally in an autocrine/paracrine manner to stimulate cancer cell growth. Since the anticancer activity of gamma-tocotrienol has been shown to be mediated in part through the disruption of lipid rafts, studies were conducted to determine the effect of gamma-tocotrienol on exosomes mitogenic biopotency. Exosomes isolated from the media of cultured T47D breast cancer cells were found to stimulate T47D cell growth in a dose-dependent manner. These growth stimulating effects were due to the high levels of heregulin contained in the exosomes that act to stimulate HER3 and HER4 activation, heterodimerization and mitogenic signaling. Exposure to 5 mu M gamma-tocotrienol resulted in the selective accumulation and disruption in the integrity of the lipid raft microdomain and a corresponding decrease in exosome heregulin content and mitogenic biopotency. These findings provide strong evidence indicating that the anticancer effects of gamma-tocotrienol are mediated, at least in part, by directly disrupting HER dimerization and signaling within the lipid rafts and indirectly by reducing exosome heregulin content and subsequent autocrine/paracrine mitogenic stimulation. (C) 2017 Elsevier Inc. All rights reserved.