Sulphoraphane, a naturally occurring isothiocyanate induces apoptosis in breast cancer cells by targeting heat shock proteins
Sulphoraphane, a naturally occurring isothiocyanate induces apoptosis in breast cancer cells by targeting heat shock proteins
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DOI：
10.1016/j.bbrc.2012.09.006
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发表时间：
2012-10-12
影响因子：
3.1
通讯作者：
Roy, Madhumita
中科院分区：
文献类型：
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作者：
Sarkar, Ruma;Mukherjee, Sutapa;Roy, Madhumita
热休克蛋白(HSPs)作为分子伴侣参与蛋白质的折叠、聚集、转运和/或稳定，通过caspase依赖和/或非依赖途径抑制细胞凋亡。热休克蛋白在多种人类肿瘤中过表达，与肿瘤细胞的增殖、分化、侵袭和转移有关。HSPs，特别是27、70、90和转录因子热休克因子1(HSF1)在乳腺癌的病因学中起关键作用，可被认为是潜在的治疗靶点。本研究旨在研究天然异硫氰酸酯萝卜硫醚对两种不同乳腺癌细胞株MCF-7和MDA-MB-231中HSPs(27，70，90)和HSF1表达的影响，以及对正常乳腺上皮细胞株MCF-12F中表达野生型和突变型p53的细胞的影响。进一步研究HSPs和HSF1的调控是否通过改变P53、p21和一些凋亡蛋白如Bcl2、Bax、Bid、Bad、Apaf-1和AIF的表达而诱导细胞凋亡。萝卜硫素可下调HSP70、90和HSF1的表达，但对HSP27的影响不明显。HSP抑制的结果是p21上调，与P53状态无关。BAX、Bad、APAF-1、AIF表达上调，而Bc1-2表达下调，且MCF-7较MDA-MB-231作用更明显。然而。观察到Bid的表达几乎没有变化。Bcl2Bax比值的改变导致细胞色素c从线粒体释放，caspase3和caspase9被激活，这与细胞凋亡指数值一致。因此，萝卜硫素可以被认为是热休克蛋白调节乳腺癌细胞凋亡的有效诱导剂。(C)2012 Elsevier Inc.保留所有权利。
Heat shock proteins (HSPs) are involved in protein folding, aggregation, transport and/or stabilization by acting as a molecular chaperone, leading to inhibition of apoptosis by both caspase dependent and/or independent pathways. HSPs are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion and metastasis. HSPs particularly 27, 70, 90 and the transcription factor heat shock factor1 (HSF1) play key roles in the etiology of breast cancer and can be considered as potential therapeutic target. The present study was designed to investigate the role of sulphoraphane, a natural isothiocyanate on HSPs (27, 70, 90) and HSF1 in two different breast cancer cell lines MCF-7 and MDA-MB-231 cells expressing wild type and mutated p53 respectively, vis-A-vis in normal breast epithelial cell line MCF-12F. It was furthermore investigated whether modulation of HSPs and HSF1 could induce apoptosis in these cells by altering the expressions of p53, p21 and some apoptotic proteins like Bcl-2, Bax, Bid, Bad, Apaf-1 and AIF. Sulphoraphane was found to down-regulate the expressions of HSP70, 90 and HSF1, though the effect on HSP27 was not pronounced. Consequences of HSP inhibition was upregulation of p21 irrespective of p53 status. Bax, Bad, Apaf-1, AIF were upregulated followed by down-regulation of Bcl-2 and this effect was prominent in MCF-7 than in MDA-MB-231. However. very little change in the expression of Bid was observed. Alteration in Bcl-2 Bax ratio resulted in the release of cytochrome c from mitochondria and activation of caspases 3 and 9 which are in agreement with apoptotic index values. Sulphoraphane therefore can be regarded as a potent inducer of apoptosis due to HSP modulation in breast cancer cells. (C) 2012 Elsevier Inc. All rights reserved.