A novel CYR61-triggered 'CYR61-αvβ3 integrin loop' regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway
A novel CYR61-triggered 'CYR61-αvβ3 integrin loop' regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway
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DOI：
10.1038/sj.onc.1208238
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发表时间：
2005-01-27
期刊：
影响因子：
8
通讯作者：
Lupu, R
中科院分区：
文献类型：
--
作者：
Menendez, JA;Vellon, L;Lupu, R
血管生成诱导剂CYR 61在乳腺癌细胞中差异性过表达，表现出高水平的调蛋白（HRG），一种与转移性乳腺癌表型密切相关的生长因子。在这里，我们研究了CYR 61是否独立于HRG，积极调节乳腺癌细胞的生存和化疗敏感性，以及相关的途径。在HRG阴性MCF-7细胞中，CYR 61的强制表达显著上调了其自身整合素受体α（v）β（3）的表达（>200倍）。小肽模拟物α（v）β（3）整联蛋白拮抗剂显著降低CYR 61过表达MCF-7细胞的细胞活力，而对照MCF-7/V保持不敏感。从机制上讲，功能性阻断alpha（v）beta（3）特异性地消除了CYR 6诱导的ERK 1/ERK 2 MAPK的过度激活，而AKT的激活状态并没有降低。此外，CYR 61过表达使MCF-7细胞对紫杉醇诱导的细胞毒性具有显著抗性（>10倍）。值得注意的是，α（v）β（3）抑制将CYR 61诱导的紫杉醇耐药表型转化为过敏表型。因此，通过末端转移酶介导的dUTP缺口末端标记（TUNEL）试验和DNA含量的流式细胞术分析证实，在存在α（v）β（3）拮抗剂的情况下，紫杉醇诱导的凋亡性细胞死亡的增加表现出强烈的协同作用。事实上，与药理学MAPK抑制剂U 0126类似，功能性阻断alpha（v）beta（3）可协同增加细胞周期G（2）期CYR 61过表达乳腺癌细胞的比例，以及紫杉醇引起的亚G（1）亚二倍体（凋亡）细胞的出现。引人注目的是，CYR 61过表达损害了紫杉醇暴露后野生型p53的积累，而抑制alpha（v）beta（3）或ERK 1/ERK 2 MAPK信号转导完全恢复了紫杉醇诱导的p53上调。此外，CYR 61表达的反义下调废除了乳腺癌细胞工程过表达HRG的锚定非依赖性生长，并显着增加其对紫杉醇的敏感性。我们的数据提供的证据表明，CYR 61是足以促进乳腺癌细胞增殖，细胞存活，并通过α（v）β（3）-激活ERK 1/ERK 2 MAPK信号紫杉醇耐药。在乳腺癌的上皮区室中鉴定出“CYR 61-α（v）β（3）自分泌环”，这强烈表明靶向α（v）β（3）可以同时防止乳腺癌血管生成、生长和化疗耐药性。
The angiogenic inducer CYR61 is differentially over-expressed in breast cancer cells exhibiting high levels of Heregulin (HRG), a growth factor closely associated with a metastatic breast cancer phenotype. Here, we examined whether CYR61, independently of HRG, actively regulates breast cancer cell survival and chemosensitivity, and the pathways involved. Forced expression of CYR61 in HRG-negative MCF-7 cells notably upregulated the expression of its own integrin receptor alpha(v)beta(3) (>200 times). Small peptidomimetic alpha(v)beta(3) integrin antagonists dramatically decreased cell viability of CYR61-overexpressing MCF-7 cells, whereas control MCF-7/V remained insensitive. Mechanistically, functional blockade of alpha(v)beta(3) specifically abolished CYR6-induced hyperactivation of ERK1/ERK2 MAPK, whereas the activation status of AKT did not decrease. Moreover, CYR61 overexpression rendered MCF-7 cells significantly resistant (>10-fold) to Taxol-induced cytotoxicity. Remarkably, alpha(v)beta(3) inhibition converted the CYR61-induced Taxol-resistant phenotype into a hypersensitive one. Thus, the augmentation of Taxol-induced apoptotic cell death in the presence of alpha(v)beta(3) antagonists demonstrated a strong synergism as verified by the terminal transferase-mediated dUTP nick-end labeling (TUNEL) assay and by flow cytometric analysis for DNA content. Indeed, functional blockade of alpha(v)beta(3), similarly to the pharmacological MAPK inhibitor U0126, synergistically increased both the proportion of CYR61-overexpressing breast cancer cells in the G(2) phase of the cell cycle and the appearance of sub-G(1) hypodiploid (apoptotic) cells caused by Taxol. Strikingly, CYR61 overexpression impaired the accumulation of wild-type p53 following Taxol exposure, while inhibition of alpha(v)beta(3) or ERK1/ERK2 MAPK signalings completely restored Taxol-induced upregulation of p53. Moreover, antisense downregulation of CYR61 expression abolished the anchorage-independent growth of breast cancer cells engineered to overexpress HRG, and significantly increased their sensitivity to Taxol. Our data provide evidence that CYR61 is sufficient to promote breast cancer cell proliferation, cell survival, and Taxol resistance through a alpha(v)beta(3)-activated ERK1/ERK2 MAPK signaling. The identification of a 'CYR61-alpha(v)beta(3) autocrine loop' in the epithelial compartment of breast carcinoma strongly suggests that targeting alpha(v)beta(3) may simultaneously prevent breast cancer angiogenesis, growth, and chemo resistance.