Metabolic patterns and biotransformation activities of resveratrol in human glioblastoma cells: relevance with therapeutic efficacies.
Metabolic patterns and biotransformation activities of resveratrol in human glioblastoma cells: relevance with therapeutic efficacies.
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人胶质母细胞瘤细胞中白藜芦醇的代谢模式和生物转化活性：与治疗效果的相关性
DOI：
10.1371/journal.pone.0027484
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Shu XH;Li H;Sun XX;Wang Q;Sun Z;Wu ML;Chen XY;Li C;Kong QY;Liu J
背景：反式白藜芦醇，而不是其生物转化的单硫酸盐代谢产物，通过抑制STAT3的激活而发挥抗髓母细胞瘤的作用。然而，由于某些未知的原因，它对人胶质母细胞瘤细胞的作用是不同的(S)。方法/主要研究结果以白藜芦醇敏感的人髓母细胞瘤细胞株UW228-3和原代培养的大鼠脑细胞/外周血为对照，通过多种实验方法阐明白藜芦醇对人胶质母细胞瘤细胞LN-18的作用及其与代谢模式(S)、脑相关硫基转移酶/SULT表达的关系以及信号转导和活化信号转导蛋白抑制物(PIAS3)的状态。同时，用免疫组织化学方法检测SULT1A1、1C2和4A1在人脑胶质母细胞瘤中的表达。结果表明，100uM白藜芦醇处理的LN-18细胞产生与UW228-3细胞相同的代谢物，而在负离子模式下，外周血细胞中发现额外的403.0992分子量的代谢物。白藜芦醇处理的LN-18和PBC细胞既没有发现生长停滞，也没有发现凋亡。白藜芦醇作用后，LN-18细胞中SULT1A1、1C2和4A1的表达水平比UW228-3细胞中的表达水平更高，接近外周血中的水平。免疫组织化学染色显示，42.0%、27.1%和19.6%的胶质母细胞瘤组织中SULT1A1、1C2和4A1的表达水平与癌旁组织相似。与UW228-3细胞不同的是，在白藜芦醇处理的LN-18细胞中，STAT3信号仍然被激活，其蛋白抑制剂PIAS3被限制在胞浆中。白藜芦醇处理的PBCs中未观察到STAT3和PIAS3的核转位。用STAT3化学抑制剂AG490处理后，LN-18和UW228-3细胞的大部分在48小时内发生了凋亡，而外周血细胞则没有。结论/意义LN-18胶质母细胞瘤细胞对白藜芦醇不敏感，原因是白藜芦醇诱导的脑相关sULT表达增加，白藜芦醇不足以抑制激活的STAT3信号转导，缺乏PIAS3核转位。外周血细胞的研究结果表明，有效抗癌剂量的白藜芦醇对正常脑细胞几乎没有副作用。
Background Trans-resveratrol rather than its biotransformed monosulfate metabolite exerts anti-medulloblastoma effects by suppressing STAT3 activation. Nevertheless, its effects on human glioblastoma cells are variable due to certain unknown reason(s). Methodology/Principal Findings Citing resveratrol-sensitive UW228-3 medulloblastoma cell line and primarily cultured rat brain cells/PBCs as controls, the effect of resveratrol on LN-18 human glioblastoma cells and its relevance with metabolic pattern(s), brain-associated sulfotransferase/SULT expression and the statuses of STAT3 signaling and protein inhibitor of activated STAT3 (PIAS3) were elucidated by multiple experimental approaches. Meanwhile, the expression patterns of three SULTs (SULT1A1, 1C2 and 4A1) in human glioblastoma tumors were profiled immunohistochemically. The results revealed that 100 µM resveratrol-treated LN-18 generated the same metabolites as UW228-3 cells, while additional metabolite in molecular weight of 403.0992 in negative ion mode was found in PBCs. Neither growth arrest nor apoptosis was found in resveratrol-treated LN-18 and PBC cells. Upon resveratrol treatment, the levels of SULT1A1, 1C2 and 4A1 expression in LN-18 cells were more up-regulated than that expressed in UW228-3 cells and close to the levels in PBCs. Immunohistochemical staining showed that 42.0%, 27.1% and 19.6% of 149 glioblastoma cases produced similar SULT1A1, 1C2 and 4A1 levels as that of tumor-surrounding tissues. Unlike the situation in UW228-3 cells, STAT3 signaling remained activated and its protein inhibitor PIAS3 was restricted in the cytosol of resveratrol-treated LN-18 cells. No nuclear translocation of STAT3 and PIAS3 was observed in resveratrol-treated PBCs. Treatment with STAT3 chemical inhibitor, AG490, committed majority of LN-18 and UW228-3 cells but not PBCs to apoptosis within 48 hours. Conclusions/Significance LN-18 glioblastoma cells are insensitive to resveratrol due to the more inducible brain-associated SULT expression, insufficiency of resveratrol to suppress activated STAT3 signaling and the lack of PIAS3 nuclear translocation. The findings from PBCs suggest that an effective anticancer dose of resveratrol exerts little side effect on normal brain cells.
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影响因子：
4.8
作者：
Ogata, Yoshitaka;Osaki, Tadashi;Kawase, Ichiro
通讯作者：
Kawase, Ichiro
DOI：
10.3322/caac.20069
发表时间：
2010-05
期刊：
CA: a cancer journal for clinicians
影响因子：
--
作者：
Van Meir EG;Hadjipanayis CG;Norden AD;Shu HK;Wen PY;Olson JJ
通讯作者：
Olson JJ
影响因子：
3.7
作者：
Ganapathy S;Chen Q;Singh KP;Shankar S;Srivastava RK
通讯作者：
Srivastava RK
DOI：
10.1158/1078-0432.ccr-08-0618
发表时间：
2008-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brantley EC;Nabors LB;Gillespie GY;Choi YH;Palmer CA;Harrison K;Roarty K;Benveniste EN
通讯作者：
Benveniste EN
影响因子：
3.9
作者：
Salman, Emily D.;Kadlubar, Susan A.;Falany, Charles N.
通讯作者：
Falany, Charles N.