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首页> 外文期刊>Life sciences >Orthovanadate-induced cell death in RET/PTC1-harboring cancer cells involves the activation of caspases and altered signaling through PI3K/Akt/mTOR.
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Orthovanadate-induced cell death in RET/PTC1-harboring cancer cells involves the activation of caspases and altered signaling through PI3K/Akt/mTOR.

机译：RET / PTC1 - 封闭癌细胞中的正交酸盐诱导的细胞死亡涉及通过PI3K / AKT / MTOR激活半胱天盒并改变信号传导。

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AIMS: Oncogenic RET/PTC1 chromosomal rearrangements are hallmarks of thyroid papillary carcinoma. The resulting protein, mainly through tyrosine 451, is responsible for the activation of pathways controlling cell survival, including the PI3K/Akt/mTOR cascade. Vanadium compounds were shown to have anti-neoplastic potential. However, reports about their mechanism of action are contradictory, particularly in what concerns the signaling mediators that are involved. Here, the aim was to characterize the effects of orthovanadate in thyroid cancer cells harboring RET/PTC1. MAIN METHODS: Growth behavior of orthovanadate-treated cells was evaluated by the sulphorhodamine B assay, cell cycle analysis and Terminal Transferase dUTP Nick End Labeling (TUNEL). Mitochondrial parameters such as the transmembrane potential and production of reactive oxygen species (ROS) were also assessed. Western blot was used to study cellular signaling. KEY FINDINGS: Low doses of the compound induce a pro-proliferative response. In contrast, treatment with inhibitory concentrations of orthovanadate results in increased phosphorylation of tyrosine 451 of RET/PTC1 and activation of the mTOR/S6R branch of the PI3K/Akt signaling pathway. These concentrations of the drug also induce typical features of apoptosis including DNA fragmentation, loss of mitochondrial membrane potential, production of ROS and activation of caspase-3. Addition of the glial cell line-derived neutrophic factor, a pro-survival stimulator that acts through RET, could not completely block orthovanadate-induced growth inhibition and cell death. SIGNIFICANCE: In this model, orthovanadate induces caspase-dependent apoptosis and interferes with the PI3K/Akt/mTOR cascade. This work provides characterization of the effects of orthovanadate and underlines the possibility of its usefulness as a cell death modulator.
机译：目的：致癌物质RET / PTC1染色体重排是甲状腺乳头状癌的标志。所得蛋白质主要通过酪氨酸451，负责激活控制细胞存活的途径，包括PI3K / AKT / MTOR级联。显示钒化合物具有抗肿瘤潜力。但是，关于他们行动机制的报道是矛盾的，特别是涉及所涉及的信号调解器的矛盾。在这里，目的是表征OrthovanaTate在含RET / PTC1的甲状腺癌细胞中的作用。主要方法：通过硫代胺B测定，细胞周期分析和末端转移酶DUTP缺口末端标记（TUNEL）评估脱甘露胺处理细胞的生长行为。还评估了线粒体参数，例如跨膜电位和反应性氧（ROS）的产生。用于研究蜂窝信号传导的Western印迹。主要发现：低剂量的化合物诱导促进增殖性反应。相反，抑制抑制浓度的正交浓度的处理导致RET / PTC1的酪氨酸451的磷酸化增加，并激活PI3K / AKT信号通路的MTOR / S6R分支。这些药物的浓度也诱导凋亡的典型特征，包括DNA碎片，线粒体膜势丧失，ROS的产生和Caspase-3的活化。添加胶质细胞系衍生的嗜鼻剂因子，一种通过RET的促求刺激剂，不能完全阻止正交酸盐诱导的生长抑制和细胞死亡。意义：在该模型中，OrthovanaDate诱导依赖性凋亡，并干扰PI3K / AKT / MTOR级联。这项工作规定了脱钒酸盐的影响，并强调其用途作为细胞死亡调制器的可能性的效果。

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