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首页> 外文期刊>The Journal of Nutritional Biochemistry >Curcumin, but not curcumin-glucuronide, inhibits Smad signaling in TGF beta-dependent bone metastatic breast cancer cells and is enriched in bone compared to other tissues
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Curcumin, but not curcumin-glucuronide, inhibits Smad signaling in TGF beta-dependent bone metastatic breast cancer cells and is enriched in bone compared to other tissues

机译：姜黄素，但不是姜黄素 - 葡糖酸，抑制TGFβ依赖性骨转移乳腺癌细胞中的Smad信号传导，与其他组织相比，富含骨骼

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摘要

Breast cancer (BCa) bone metastases (BMETs) drive osteolysis via a feed-forward loop involving tumoral secretion of osteolytic factors (e.g., PTHrP) induced by bone-matrix-derived growth factors (e.g., TGF beta). In prior experiments, turmeric-derived curcumin inhibited in vivo BMET progression and in vitro TGF beta/Smad-signaling in a TGF beta-stimulated PTHrP-dependent human xenograft BCa BMET model (MDA-SA cells). However, it is unclear whether curcumin or curcumin-glucuronide mediates in vivo protection since curcumin-glucuronide is the primary circulating metabolite in rodents and in humans. Thus, effects of curcumin vs. curcumin-glucuronide on Smad-dependent TGF beta signaling were compared in a series of BCa cell lines forming TGF beta-dependent BMET in murine models, and tissue-specific metabolism of curcumin in mice was examined by LC-MS. While curcumin inhibited TGF beta-receptor-mediated Smad2/3 phosphorylation in all BCa cells studied (human MDA-SA, MDA-1833, MDA-2287 and murine 4T1 cells), curcumin-glucuronide did not. Similarly, curcumin, but not curcumin-glucuronide, blocked TGF beta-stimulated secretion of PTHrP from MDA-SA and 4T1 cells. Because the predominant serum metabolite, curcumin-glucuronide, lacked bioactivity, we examined tissue-specific metabolism of curcumin in mice. Compared to serum and other organs, free curcumin (both absolute and percentage of total) was significantly increased in bone, which was also a rich source of enzymatic deglucuronidation activity. Thus, curcumin, and not curcumin-glucuronide, appears to inhibit bone-tropic BCa cell TGF beta-signaling and to undergo site-specific activation (deconjugation) within the bone microenvironment. These findings suggest that circulating curcumin-glucuronide may act as a prodrug that preferentially targets bone, a process that may contribute to the bone-protective effects of curcumin and other highly glucuronidated dietary polyphenols. (C) 2018 Elsevier Inc. All rights reserved.
机译：乳腺癌（BCA）骨转移（BMET）通过涉及由骨 - 基质衍生的生长因子（例如TGFβ）诱导的骨溶解因子（例如，PTHRP）的肿瘤分泌的前馈回路驱动骨液。在现有实验中，姜黄衍生的姜黄素在体内BMET进展中抑制，在TGFβ刺激的PTHRP依赖性人异种移植BCA BMET模型中（MDA-SA细胞）中的体外TGFβ/ Smad-Signing。然而，目前尚不清楚姜黄素或姜黄素 - 葡糖醛酸蛋白酶是否在体内保护中介导，因为姜黄素 - 葡糖醛酸是啮齿动物和人类中的主要循环代谢物。因此，在一系列BCA细胞系中将姜黄素与姜黄素 - 葡萄糖醛酰胺对依赖于鼠依赖于鼠模型的一系列BCA细胞系的影响进行比较，并通过LC-检查小鼠中姜黄素的组织特异性代谢。多发性硬化症。虽然姜黄素抑制TGFβ受体介导的Smad2 / 3在所研究的所有BCA细胞中的Smad2 / 3磷酸化（人MDA-SA，MDA-1833，MDA-2287和鼠4T1细胞），姜黄素 - 葡萄糖醛酸酯没有。类似地，姜黄素，但不是姜黄素 - 葡糖醛酸，抑制来自MDA-SA和4T1细胞的PTHRP的TGFβ刺激的分泌。因为染色血清代谢物，姜黄素 - 葡糖酸缺乏生物活性，所以我们检查了小鼠中姜黄素的组织特异性代谢。与血清和其他器官相比，骨中的游离姜黄素（绝对和总量的百分比）显着增加，这也是酶促脱氮活性的丰富来源。因此，姜黄素和不姜黄素 - 葡糖醛酸蛋白似乎抑制骨 - 热带BCA细胞TGFβ-信号传导并在骨微环境中进行特异性特异性活化（Deconjugation）。这些发现表明，循环姜黄素 - 葡糖醛酸酯可以作为优先靶向骨骼的前药，这是可能有助于姜黄素和其他高葡糖醛尿酸膳食多酚的骨保护作用的过程。 （c）2018年Elsevier Inc.保留所有权利。

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