Sulforaphane inhibits pancreatic cancer through disrupting Hsp90-p50(Cdc37) complex and direct interactions with amino acids residues of Hsp90.
Sulforaphane inhibits pancreatic cancer through disrupting Hsp90-p50(Cdc37) complex and direct interactions with amino acids residues of Hsp90.
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DOI：
10.1016/j.jnutbio.2011.11.004
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发表时间：
2012-12
期刊：
影响因子：
--
通讯作者：
Sun D
中科院分区：
文献类型：
--
作者：
Li Y;Karagöz GE;Seo YH;Zhang T;Jiang Y;Yu Y;Duarte AM;Schwartz SJ;Boelens R;Carroll K;Rüdiger SG;Sun D
萝卜硫素[1-异硫氰酸基-4-（甲基亚磺酰基）丁烷]是一种来源于十字花科蔬菜的异硫氰酸酯，具有很强的化学预防活性。我们分析了萝卜硫素对胰腺癌细胞增殖的影响。萝卜硫素在体外抑制胰腺癌细胞生长，IC 50约为10-15 μM，并诱导细胞凋亡。在胰腺癌异种移植小鼠模型中，给予莱菔硫烷显示出显著的肿瘤生长抑制，而未观察到明显的毒性。我们发现萝卜硫素诱导胰腺癌细胞中热休克蛋白90（Hsp 90）客户蛋白的降解，并阻断Hsp 90与其辅伴侣p50 Cdc 37的相互作用。使用核磁共振光谱（NMR）与异亮氨酸特异性标记策略，我们克服了传统NMR的蛋白质大小的限制，并研究了萝卜硫素与全长热休克蛋白90二聚体（170 kDa）在溶液中的相互作用。NMR揭示了多个化学位移片2和相邻的环在Hsp 90 N-末端结构域孵育后的Hsp 90与莱菔硫烷。液相色谱-质谱联用（LC-MS）进一步绘制了该区域中用莱菔硫烷标记的短肽。这些数据表明，萝卜硫素的一个新的机制，破坏蛋白质-蛋白质相互作用的热休克蛋白90复合物的化学预防活性。
Sulforaphane [1-isothiocyanato-4-(methyl-sulfinyl) butane)], an isothiocyanate derived from cruciferous vegetables, has been shown to possess potent chemopreventive activity. We analyzed the effect of sulforaphane on the proliferation of pancreatic cancer cells. Sulforaphane inhibited pancreatic cancer cell growth in vitro with the IC50's around 10-15 μM and induced apoptosis. In pancreatic cancer xenograft mouse model, administration of sulforaphane showed remarkable inhibition of tumor growth without apparent toxicity noticed. We found that sulforaphane induced the degradation of heat shock protein 90 (Hsp90) client proteins and blocked the interaction of Hsp90 with its cochaperone p50Cdc37 in pancreatic cancer cells. Using Nuclear Magnetic Resonance Spectroscopy (NMR) with an isoleucine-specific labeling strategy, we overcame the protein size limit of conventional NMR and studied the interaction of sulforaphane with full-length Hsp90 dimer (170 kDa) in solution. NMR revealed multiple chemical shifts in sheet 2 and the adjacent loop in Hsp90 N-terminal domain after incubation of Hsp90 with sulforaphane. Liquid Chromatography coupled to Mass Spectrometry (LC-MS) further mapped a short peptide in this region that was tagged with sulforaphane. These data suggest a new mechanism of sulforaphane that disrupts protein-protein interaction in Hsp90 complex for its chemopreventive activity.
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影响因子：
5.7
作者：
Kim SH;Singh SV
通讯作者：
Singh SV
影响因子：
3.5
作者：
通讯作者：
--
DOI：
10.1158/1078-0432.ccr-09-2937
发表时间：
2010-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Li Y;Zhang T;Korkaya H;Liu S;Lee HF;Newman B;Yu Y;Clouthier SG;Schwartz SJ;Wicha MS;Sun D
通讯作者：
Sun D
DOI：
10.1073/pnas.0903503106
发表时间：
2009-05-26
影响因子：
11.1
作者：
Bertelsen, Eric B.;Chang, Lyra;Zuiderweg, Erik R. P.
通讯作者：
Zuiderweg, Erik R. P.
影响因子：
20.3
作者：
Rao, Rekha;Fiskus, Warren;Bhalla, Kapil
通讯作者：
Bhalla, Kapil