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首页> 外文期刊>Cellular Signalling >Panobinostat (LBH589) inhibits Wnt/beta-catenin signaling pathway via upregulating APCL expression in breast cancer
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Panobinostat (LBH589) inhibits Wnt/beta-catenin signaling pathway via upregulating APCL expression in breast cancer

机译：Panobinostat（LBH589）通过在乳腺癌中提升APCL表达来抑制WNT /β-连环蛋白信号传导途径

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摘要

Breast cancer is the most common malignant disease among women worldwide and the novel therapeutic agents are urgently needed. Panobinostat (LBH589), a pan-HDACs inhibitor, has shown promising anti-tumor effect in recent years. However, the targets of this compound are largely unclear because of its low selectivity. In consideration of the transcription promoting activity of panobinostat, we speculated that specific tumor suppressor genes might be upregulated after panobinostat treatment. In this study, we verified the inhibition effect of panobinostat in different subtypes of breast cancer cells in vivo and in vitro. We found that panobinostat suppressed proliferation, migration as well as invasion, and induced apoptosis in both TNBC and non-TNBC cells. Consistently, panobinostat inhibited breast cancer growth and metastasis in mouse models. Mechanistically, we found APCL transcription and expression was significantly upregulated in panobinostat treated cells by RNA microarray analysis, while knockdown of APCL resulted in reduced sensitivity to panobinostat in breast cancer cells. APCL is a wnt/beta-catenin pathway regulator that promotes beta-catenin ubiquitylation and degradation. We found that panobinostat inhibited beta-catenin expression by increasing its ubiquitylation and thus reducing its half-life. In addition, the expression of beta-catenin activated targets including c-Jun, c-Myc, Cyclin D1 and CD44 were also decreased by panobinostat treatment in breast cancer cells. These results suggested that panobinostat inhibited tumor growth and metastasis via upregulating APCL expression in breast cancer cells, which was a novel and crucial mechanism of panobinostat.
机译：乳腺癌是全球女性中最常见的恶性疾病，迫切需要新的治疗剂。 Panobinostat（LBH589）是潘HDACS抑制剂，近年来展示了有前途的抗肿瘤作用。然而，由于其选择性低，该化合物的靶标在很大程度上不清楚。考虑到Panobinostat的转录促进活性，我们推测了Panobostat治疗后可能上调特异性肿瘤抑制基因。在这项研究中，我们验证了Panobinostat在体内和体外不同乳腺癌细胞亚型亚型的抑制作用。我们发现Panobinostat抑制了TNBC和非TNBC细胞中的增殖，迁移以及侵袭，并诱导细胞凋亡。始终如一地，Panobinostat抑制了小鼠模型中的乳腺癌生长和转移。机械地，通过RNA微阵列分析，我们发现在Panobinostat处理细胞中显着上调APCL转录和表达，而APCL的敲低导致乳腺癌细胞中Panobinostat的敏感性降低。 APCL是WNT /β-连环蛋白途径调节剂，促进β-连环蛋白泛酸蛋白蛋白泛酸纤维化和降解。我们发现Panobinostat通过增加其泛醌抑制β-连环蛋白表达，从而减少其半衰期。此外，在乳腺癌细胞中的Panobinostat治疗也降低了包括C-Jun，C-Myc，Cyclin D1和CD44的β-连环蛋白活化靶标的表达。这些结果表明，Panobinostat通过上调乳腺癌细胞中的APCL表达来抑制肿瘤生长和转移，这是Panobinostat的一种新颖和关键的机制。

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  • 来源
    《Cellular Signalling》 |2019年第2019期|共14页
  • 作者

    Qin Ge; Li Yizhuo; Xu Xiangdong; Wang Xin; Zhang Kai; Tang Yanlai; Qiu Huijuan; Shi Dingbo; Zhang Changlin; Long Qian; Lee Kaping; Zhai Qinglian; Wang Shusen; Chen Miao; Deng Wuguo;

  • 作者单位

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Thyroid &

    Breast Surg Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Pediat Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

    Sun Yat Sen Univ Canc Ctr Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China Guangzhou Guangdong Peoples R China;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞形态学;
  • 关键词

    Panobinostat; APCL; Wnt/beta-catenin signaling pathway; Breast cancer;

    机译：Panobinostat;APCL;wnt / beta-catenin信号通路;乳腺癌;

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