Panepoxydone targets NF-kB and FOXM1 to inhibit proliferation, induce apoptosis and reverse epithelial to mesenchymal transition in breast cancer.
Panepoxydone targets NF-kB and FOXM1 to inhibit proliferation, induce apoptosis and reverse epithelial to mesenchymal transition in breast cancer.
复制标题
DOI：
10.1371/journal.pone.0098370
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Dean-Colomb W
中科院分区：
文献类型：
--
作者：
Arora R;Yates C;Gary BD;McClellan S;Tan M;Xi Y;Reed E;Piazza GA;Owen LB;Dean-Colomb W
三阴性乳腺癌 (TNBC) 是一个高度多样化的群体，与侵袭性表型相关。由于其异质性和缺乏明确的分子靶点，其治疗一直具有挑战性。因此，迫切需要鉴定具有治疗应用的新型药物。 NF-κB 在许多乳腺癌中过度表达；因此，NF-κB 通路的失活可以作为治疗靶点。在此，我们首次报道了panepoxydone (PP)（一种从食用蘑菇中分离出来的 NF-κB 抑制剂）在几种乳腺癌细胞系中的抗肿瘤活性。我们研究了 PP 对 MCF-7 和 TNBC 细胞系 MDA-MB-231、MDA-MB-468 和 MDA-MB-453 中细胞生长、迁移侵袭、凋亡和 EMT 相关蛋白表达的影响。在所有细胞系中均观察到显着的抗肿瘤活性，并以细胞系特异性方式注意到差异反应。在所有测试的细胞系中，PP 处理均导致显着的细胞毒性、侵袭、迁移减少和细胞凋亡增加。在 PP 处理的乳腺癌细胞中，Bax 和裂解的 PARP 上调，Bcl-2、生存素、细胞周期蛋白 D1 和 caspase 3 下调。 PP的抗肿瘤作用似乎与其抑制NF-κB抑制剂(IκBα)磷酸化并在细胞质中积累有关。 PP 治疗还下调 FOXM1，从而导致 EMT 逆转。沉默 NF-kB 和 FOXM1 后获得了类似的结果。总之，这些研究首次表明 PP 对乳腺癌细胞，特别是 TNBC 细胞具有抗肿瘤活性。此外，它强调了这样一个概念，即 TNBC 的最佳治疗需要注意各种 TNBC 亚型对治疗药物的不同敏感性。这些结果表明，PP 可能是一种潜在有效的乳腺癌化学预防或治疗剂。然而，还需要更多的研究来更全面地阐明 PP 的抗肿瘤作用机制。
Triple-negative breast cancer (TNBC) is a highly diverse group that is associated with an aggressive phenotype. Its treatment has been challenging due to its heterogeneity and absence of well-defined molecular targets. Thus, there is an urgent need to identify novel agents with therapeutic application. NF-κB is over-expressed in many breast cancers; thus, inactivation of the NF-κB pathway could serve as a therapeutic target. Here we report for the first time the anti-tumor activity of panepoxydone (PP), a NF-κB inhibitor isolated from an edible mushroom, in several breast cancer cell lines. We investigated the effects of PP on cell growth, migration-invasion, apoptosis and EMT-related proteins expression in MCF-7 and TNBC cell lines MDA-MB-231, MDA-MB-468 and MDA-MB-453. Significant antitumor activity was seen in all cell lines, with differential responses noted in cell-line specific manner. Treatment with PP resulted in significant cytotoxicity, decreased invasion, migration and increased apoptosis in all cell lines tested. Up-regulation of Bax and cleaved PARP and down-regulation of Bcl-2, survivin, cyclin D1 and caspase 3 were noted in PP-treated breast cancer cells. The antitumor effect of PP appeared related to its ability to inhibit the phosphorylation of inhibitor of NF-κB (IκBα) with cytoplasmic accumulation. PP treatment also down-regulated FOXM1 which resulted in a reversal of EMT. Similar results were obtained after silencing of NF-kB and FOXM1. Altogether, these studies show, for the first time the antitumor activity of PP against breast cancer cells, in particular TNBC cells. Furthermore, it highlights the concept that optimal treatment of TNBC warrants attention to the differential sensitivity of various TNBC subtypes to therapeutic agents. These results suggest that the PP may be a potentially effective chemopreventive or therapeutic agent against breast cancer. However, additional studies are required to more fully elucidate the mechanism of antitumor effect of PP.
登录
查看更多内容
DOI：
10.1016/j.biocel.2007.07.011
发表时间：
2007-01-01
影响因子：
4
作者：
Guarino, Marcello
通讯作者：
Guarino, Marcello
影响因子：
3.7
作者：
Gong Y;Li Y;Abdolmaleky HM;Li L;Zhou JR
通讯作者：
Zhou JR
影响因子：
4
作者：
Bao, Bin;Wang, Zhiwei;Ali, Shadan;Kong, Dejuan;Banerjee, Sanjeev;Ahmad, Aamir;Li, Yiwei;Azmi, Asfar S.;Miele, Lucio;Sarkar, Fazlul H.
通讯作者：
Sarkar, Fazlul H.
影响因子：
4
作者：
Ahmad, Aamir;Banerjee, Sanjeev;Sarkar, Fazlul H.
通讯作者：
Sarkar, Fazlul H.
DOI：
10.1073/pnas.0903392106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Caldas-Lopes, Eloisi;Cerchietti, Leandro;Chiosis, Gabriela
通讯作者：
Chiosis, Gabriela