Gamma tocotrienol targets tyrosine phosphatase SHP2 in mammospheres resulting in cell death through RAS/ERK pathway
Gamma tocotrienol targets tyrosine phosphatase SHP2 in mammospheres resulting in cell death through RAS/ERK pathway
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DOI：
10.1186/s12885-015-1614-1
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发表时间：
2015-08-28
期刊：
影响因子：
3.8
通讯作者：
Yu, Chengzhong
中科院分区：
文献类型：
--
作者：
Gu, Wenyi;Prasadam, Indira;Yu, Chengzhong
背景：越来越多的证据支持肿瘤干细胞的概念，肿瘤干细胞在肿瘤的发生、生长和转移中起重要作用。因此，干细胞被认为是未来癌症治疗的目标。为了实现这一目标，确定CSCs的潜在治疗靶点是至关重要的。方法：我们使用维生素E的天然产物--生育三烯醇(Gamma-T3)来治疗结肠癌和宫颈癌的乳房和球体。用Western blotting和实时荧光定量RT-PCR方法鉴定乳腺组织中的γ-T3基因和蛋白靶点。结果：我们发现乳腺细胞生长受到抑制，呈剂量依赖关系，在高剂量时完全抑制。伽马-T3还抑制了另外两种人类上皮性癌症--结肠癌和子宫颈癌的球体生长。我们的结果提示，含Src同源2结构域的磷酸酶1(SHP1)和2(SHP2)都受到γ-T3的影响，同时伴随着K-和H-Ras基因表达的降低以及ERK蛋白的磷酸化，并呈剂量依赖关系。相反，自我更新基因TGF-β和LIF的表达以及ESR信号通路不受治疗的影响。结论：SHP1和SHP2是乳腺CSCs潜在的治疗靶点，Gamma-T3是未来乳腺癌治疗的一种有前景的天然药物。
Background: There is increasing evidence supporting the concept of cancer stem cells (CSCs), which are responsible for the initiation, growth and metastasis of tumors. CSCs are thus considered the target for future cancer therapies. To achieve this goal, identifying potential therapeutic targets for CSCs is essential.Methods: We used a natural product of vitamin E, gamma tocotrienol (gamma-T3), to treat mammospheres and spheres from colon and cervical cancers. Western blotting and real-time RT-PCR were employed to identify the gene and protein targets of gamma-T3 in mammospheres.Results: We found that mammosphere growth was inhibited in a dose dependent manner, with total inhibition at high doses. Gamma-T3 also inhibited sphere growth in two other human epithelial cancers, colon and cervix. Our results suggested that both Src homology 2 domain-containing phosphatase 1 (SHP1) and 2 (SHP2) were affected by gamma-T3 which was accompanied by a decrease in K-and H-Ras gene expression and phosphorylated ERK protein levels in a dose dependent way. In contrast, expression of self-renewal genes TGF-beta and LIF, as well as ESR signal pathways were not affected by the treatment. These results suggest that gamma-T3 specifically targets SHP2 and the RAS/ERK signaling pathway.Conclusions: SHP1 and SHP2 are potential therapeutic targets for breast CSCs and gamma-T3 is a promising natural drug for future breast cancer therapy.