Alawin Osama A, Ahmed Rayan A, Dronamraju Venkateshwararao, Briski Karen P, Sylvester Paul W
School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209, USA.
School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209, USA.
J Nutr Biochem. 2017 Oct;48:83-93. doi: 10.1016/j.jnutbio.2017.06.013. Epub 2017 Jul 10.
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 γ-tocotrienol has been shown to be mediated in part through the disruption of lipid rafts, studies were conducted to determine the effect of γ-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 μM γ-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 γ-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.
神经调节蛋白是一种激活HER3和HER4受体的强效配体，其过表达在乳腺癌患者化疗耐药性的发展中起重要作用。癌细胞释放的外泌体是源自脂筏向外芽生的小囊泡，携带各种促有丝分裂蛋白，然后以自分泌/旁分泌方式在局部发挥作用以刺激癌细胞生长。由于已证明γ-生育三烯酚的抗癌活性部分是通过破坏脂筏来介导的，因此开展了相关研究以确定γ-生育三烯酚对外泌体促有丝分裂生物活性的影响。从培养的T47D乳腺癌细胞培养基中分离出的外泌体被发现以剂量依赖方式刺激T47D细胞生长。这些生长刺激作用归因于外泌体中所含的高水平神经调节蛋白，其作用是刺激HER3和HER4的激活、异二聚化和促有丝分裂信号传导。暴露于5μMγ-生育三烯酚会导致脂筏微区完整性的选择性积累和破坏，以及外泌体神经调节蛋白含量和促有丝分裂生物活性相应降低。这些发现提供了有力证据，表明γ-生育三烯酚的抗癌作用至少部分是通过直接破坏脂筏内的HER二聚化和信号传导，以及间接通过降低外泌体神经调节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。
