Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms.
Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms.
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DOI：
10.1038/onc.2012.138
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发表时间：
2013-03-07
期刊：
影响因子：
8
通讯作者：
Law, B. K.
中科院分区：
文献类型：
--
作者：
Law, M. E.;Corsino, P. E.;Jahn, S. C.;Davis, B. J.;Chen, S.;Patel, B.;Pham, K.;Lu, J.;Sheppard, B.;Norgaard, P.;Hong, J.;Higgins, P.;Kim, J-S;Luesch, H.;Law, B. K.
侵袭性癌症通常在细胞质囊泡中表达e -钙粘蛋白，而不是在质膜上表达，这可能有助于这些肿瘤的侵袭性表型。目前还没有能够恢复e -钙粘蛋白在癌症中的抗侵袭功能的治疗策略。MDA-MB-231细胞是侵袭性三阴性乳腺癌的常用模型，这些细胞表达低水平的e-钙粘蛋白，并错定位于细胞质囊泡。以稳定表达野生型E-cadherin或E-cadherin与谷胱甘肽s -转移酶或绿色荧光蛋白融合的MDA-MB-231细胞系为实验系统，探讨侵袭性癌症细胞质中E-cadherin定位的机制。虽然E-cadherin的表达在体外部分地降低了细胞的侵袭，但E-cadherin主要局限于细胞质，并不能阻断相应的原位异种移植物肿瘤的侵袭。进一步研究表明糖皮质激素地塞米松和高效I类组蛋白去乙酰化酶（HDAC）抑制剂largazole共同诱导E-cadherin在三阴性乳腺癌的质膜定位，并在体外抑制细胞侵袭。地塞米松通过上调丝氨酸蛋白酶抑制剂纤溶酶原激活物抑制剂-1，阻断了CDCP1（即含CUB结构域蛋白1）蛋白（cCDCP1）的裂解形式的产生，而cCDCP1先前与CDCP1的促侵袭活性有关。与全长型相比，e -钙粘蛋白更倾向于与cCDCP1相关。相比之下，largazole不影响CDCP1的切割，但增加了E-cadherin与γ-catenin的关联。这种对E-cadherin/γ-catenin复合物的影响与非异构体选择性HDAC抑制剂trichostatin A （TSA）和vorinostat （suberoylanilide hydroxamic acid， SAHA）相同，尽管largazole比TSA更强烈地上调内源性E-cadherin水平。这些结果表明，糖皮质激素和HDAC抑制剂，这两种目前都在临床使用，通过新的互补机制共同抑制乳腺癌细胞的侵袭性，这些机制聚集在e -钙粘蛋白上。
Aggressive cancers often express E-cadherin in cytoplasmic vesicles rather than on the plasma membrane and this may contribute to the invasive phenotype of these tumors. Therapeutic strategies are not currently available that restore the anti-invasive function of E-cadherin in cancers. MDA-MB-231 cells are a frequently used model of invasive triple-negative breast cancer, and these cells express low levels of E-cadherin that is mislocalized to cytoplasmic vesicles. MDA-MB-231 cell lines stably expressing wild-type E-cadherin or E-cadherin fused to glutathione S-transferase or green fluorescent protein were used as experimental systems to probe the mechanisms responsible for cytoplasmic E-cadherin localization in invasive cancers. Although E-cadherin expression partly reduced cell invasion in vitro, E-cadherin was largely localized to the cytoplasm and did not block the invasiveness of the corresponding orthotopic xenograft tumors. Further studies indicated that the glucocorticoid dexamethasone and the highly potent class I histone deacetylase (HDAC) inhibitor largazole cooperated to induce E-cadherin localization to the plasma membrane in triple-negative breast cancers, and to suppress cellular invasion in vitro. Dexamethasone blocked the production of the cleaved form of the CDCP1 (that is, CUB domain-containing protein 1) protein (cCDCP1) previously implicated in the pro-invasive activities of CDCP1 by upregulating the serine protease inhibitor plasminogen activator inhibitor-1. E-cadherin preferentially associated with cCDCP1 compared with the full-length form. In contrast, largazole did not influence CDCP1 cleavage, but increased the association of E-cadherin with γ-catenin. This effect on E-cadherin/γ-catenin complexes was shared with the nonisoform selective HDAC inhibitors trichostatin A (TSA) and vorinostat (suberoylanilide hydroxamic acid, SAHA), although largazole upregulated endogenous E-cadherin levels more strongly than TSA. These results demonstrate that glucocorticoids and HDAC inhibitors, both of which are currently in clinical use, cooperate to suppress the invasiveness of breast cancer cells through novel, complementary mechanisms that converge on E-cadherin.
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影响因子：
8
作者：
Jeanes, A.;Gottardi, C. J.;Yap, A. S.
通讯作者：
Yap, A. S.
DOI：
10.1083/jcb.201009141
发表时间：
2011-03-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Baum B;Georgiou M
通讯作者：
Georgiou M
DOI：
10.1006/bbrc.1999.1002
发表时间：
1999-08-02
影响因子：
3.1
作者：
Hiscox, S;Jiang, WG
通讯作者：
Jiang, WG
影响因子：
5.3
作者：
Lévy, L;Wei, Y;Neuveut, C
通讯作者：
Neuveut, C
影响因子：
8
作者：
Benes, C. H.;Poulogiannis, G.;Cantley, L. C.;Soltoff, S. P.
通讯作者：
Soltoff, S. P.