Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation.
Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation.
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DOI：
10.18632/oncotarget.2634
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发表时间：
2014-12-15
期刊：
影响因子：
--
通讯作者：
Dobbelstein M
中科院分区：
文献类型：
--
作者：
Keitel U;Scheel A;Thomale J;Halpape R;Kaulfuß S;Scheel C;Dobbelstein M
从上皮到间充质表型（EMT）的转变增加了肿瘤细胞的侵袭性和克隆潜能。我们使用乳腺上皮源性细胞培养模型来评估EMT对化疗药物和凋亡刺激的细胞敏感性的影响。通过EMT的细胞获得了对化疗药物和死亡配体的耐药性。在机制上，我们发现细胞凋亡抑制剂Bcl-xL的水平在间充质细胞和上皮细胞中强烈增强，而促凋亡蛋白Bim和Puma则减少。来自乳腺癌的临床样本显示，与属于大肿瘤细胞群的细胞相比，分散到间质中细胞的Bcl-xL染色增强，表明当细胞侵入间质时，Bcl-xL表达增加。Bcl-xL是间充质细胞抗凋亡所必需的，其表达足以赋予上皮细胞这种抗性。用bh3模拟物拮抗Bcl-xL。它们成功地干扰了间充质细胞的增殖和存活，也抑制了间充质亚群培养的异种移植物肿瘤的生长。我们得出结论，增强的Bcl-xL水平赋予了EMT对细胞的抗性，并且Bcl-xL代表了针对侵袭性癌细胞的治疗的有希望的靶点。
The transition from an epithelial to a mesenchymal phenotype (EMT) confers increased invasiveness and clonogenic potential to tumor cells. We used a breast epithelium-derived cell culture model to evaluate the impact of EMT on the cellular sensitivity towards chemotherapeutics and apoptotic stimuli. Cells that had passed through an EMT acquired resistance towards chemotherapeutics and death ligands. Mechanistically, we found that the levels of the apoptosis inhibitor Bcl-xL were strongly enhanced in mesenchymal versus epithelial cells, whereas the pro-apoptotic proteins Bim and Puma were diminished. Clinical samples from breast cancer showed enhanced Bcl-xL staining in cells that had dispersed into the desmoplastic stroma, as compared to cells that were part of large tumor cell aggregates, suggesting increased Bcl-xL expression when cells invade the stroma. Bcl-xL was necessary for apoptotic resistance in mesenchymal cells, and its expression was sufficient to confer such resistance to epithelial cells. To antagonize Bcl-xL, BH3-mimetics were used. They successfully interfered with the proliferation and survival of mesenchymal cells, and also inhibited the growth of xenograft tumors raised from the mesenchymal subpopulation. We conclude that enhanced Bcl-xL levels confer resistance to cells upon EMT, and that Bcl-xL represents a promising target for therapy directed against invasive cancer cells.
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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