The cholesterol-derived metabolite dendrogenin A functionally reprograms breast adenocarcinoma and undifferentiated thyroid cancer cells
The cholesterol-derived metabolite dendrogenin A functionally reprograms breast adenocarcinoma and undifferentiated thyroid cancer cells
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DOI：
10.1016/j.jsbmb.2019.105390
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发表时间：
2019-09-01
影响因子：
4.1
通讯作者：
Silvente-Poirot, Sandrine
中科院分区：
文献类型：
--
作者：
Bauriaud-Mallet, Mathilde;Vija-Racaru, Lavinia;Silvente-Poirot, Sandrine
Dendrogenin A（DDA）是一种具有肿瘤抑制作用的哺乳动物胆固醇衍生代谢物，也是一种新的肝X受体（LXR）配体，其显示肿瘤细胞分化。在人MCF 7乳腺癌细胞中，DDA诱导的细胞分化与乳汁中发现的中性脂质和蛋白质积累增加相关，表明DDA重新激活泌乳细胞的某些功能。在正常哺乳期乳腺细胞中，碘离子通过钠/碘同向转运体（NIS）进行主动转运，碘离子（I）被分泌到乳汁中，供哺乳期新生儿用于甲状腺激素的生物合成。在本研究中，我们评估了DDA是否可能诱导MCF 7乳腺癌细胞的其他泌乳细胞特征，如MS表达和碘摄取，并将本研究扩展到乳头状B-CPAP和未分化间变性8505 c甲状腺癌细胞。此外，我们评估了DDA对参与甲状腺激素生物合成的甲状腺特异性蛋白表达的影响。我们在这里报告，DDA诱导NIS在MCF 7细胞中的表达，并通过LXR作用显著增加131-I的摄取。此外，DDA诱导两种人甲状腺癌细胞系再分化的表型、分子和功能特征，并且未分化的8505 c细胞中131-I的摄取与参与甲状腺激素生物合成的所有特异性蛋白质、TSH受体、甲状腺过氧化物酶和甲状腺球蛋白的强表达相关。在8505 c细胞中的131-I掺入由DDA以及由合成的LXR配体GW 3965刺激。总之，这些数据表明，通过DDA的乳腺癌和甲状腺癌细胞的再分化与功能性NIS表达的恢复相关，并且涉及LXR依赖性机制。这些结果为甲状腺癌的诊断以及放射性碘难治性甲状腺癌的新治疗方法的开发开辟了新的研究途径。
Dendrogenin A (DDA) is a tumor suppressor mammalian cholesterol-derived metabolite and a new class of ligand of the Liver X receptor (LXR), which displays tumor cell differentiation. In human MCF7 breast adenocarcinoma cells, DDA-induced cell differentiation was associated with an increased accumulation of neutral lipids and proteins found in milk indicating that DDA re-activates some functions of lactating cells. Active iodide transport occurs in the normal lactating mammary cells through the sodium/iodide symporter (NIS) and iodide (I) is secreted into milk to be used by the nursing newborn for thyroid hormones biosynthesis. In the present study, we assessed whether DDA may induce other characteristic of lactating cells such as MS expression and iodine uptake in MCF7 breast cancer cells and extended this study to the papillary B-CPAP and undifferentiated anaplastic 8505c thyroid cancer cells. Moreover, we evaluated DDA impact on the expression of thyroid specific proteins involved in thyroid hormone biogenesis. We report here that DDA induces NIS expression in MCF7 cells and significantly increases the uptake of 131-I by acting through the LXR. In addition, DDA induces phenotypic, molecular and functional characteristics of redifferentiation in the two human thyroid carcinoma cell lines and the uptake of 131-I in the undifferentiated 8505c cells was associated with a strong expression of all the specific proteins involved in thyroid hormone biosynthesis, TSH receptor, thyroperoxidase and thyroglobulin. 131-I incorporation in the 8505c cells was stimulated by DDA as well as by the synthetic LXR ligand, GW3965. Together these data show that the re-differentiation of breast and thyroid cancer cells by DDA, is associated with the recovery of functional NIS expression and involves an LXR-dependent mechanism. These results open new avenues of research for the diagnosis of thyroid cancers as well as the development of new therapeutic approaches for radioiodine refractory thyroid cancers.