Niclosamide sensitizes triple-negative breast cancer cells to ionizing radiation in association with the inhibition of Wnt/β-catenin signaling
Niclosamide sensitizes triple-negative breast cancer cells to ionizing radiation in association with the inhibition of Wnt/β-catenin signaling
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Niclosamide 使三阴性乳腺癌细胞对电离辐射敏感，并抑制 Wnt/β-连环蛋白信号传导。
DOI：
10.18632/oncotarget.9704
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发表时间：
2016-07-05
期刊：
影响因子：
--
通讯作者：
Chen, Honghong
中科院分区：
文献类型：
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作者：
Yin, Lina;Gao, Yun;Chen, Honghong
三阴性乳腺癌（TNBC）是最难治疗的乳腺癌之一，因为没有靶向治疗，常规细胞毒性化疗后辅助放疗是TNBC患者的标准治疗。我们在此报道了电离辐射（IR）诱导TNBC MDA-MB-231、MDA-MB-468和Hs 578 T细胞中Wnt 3a、LRP 6和β-catenin的表达，从而激活Wnt/β-catenin信号传导。此外，通过shRNA耗尽β-连环蛋白使TNBC细胞对IR敏感，而Wnt 3a蛋白或β-连环蛋白过表达的处理导致TNBC细胞的放射抗性。氯硝柳胺是一种有效的Wnt/β-catenin信号传导抑制剂，不仅抑制组成性Wnt/β-catenin信号传导，而且阻断TNBC细胞中IR诱导的Wnt/β-catenin信号传导。此外，氯硝柳胺使TNBC细胞对IR敏感，防止Wnt 3a诱导的辐射抗性，并克服TNBC细胞中β-连环蛋白诱导的辐射抗性。重要的是，与仅用局部肿瘤照射治疗相比，用氯硝柳胺和η-射线局部肿瘤照射的组合治疗的动物具有对MDA-MB-231肿瘤生长的显著抑制。这些发现表明Wnt/β-catenin信号通路在TNBC细胞辐射抗性的发展中起重要作用，并且氯硝柳胺通过抑制TNBC细胞中的Wnt/β-catenin信号通路而具有显著的辐射增敏作用。我们的研究还为氯硝柳胺在TNBC管理中的进一步临床前和临床评价提供了依据。
Triple-negative breast cancer (TNBC) is one of the most difficult breast cancers to treat because there is no targeted treatment, and conventional cytotoxic chemotherapy followed by adjuvant radiation therapy is the standard of care for patients with TNBC. We herein reported that ionizing radiation (IR) induced Wnt3a, LRP6 and beta-catenin expression and consequently activated Wnt/beta-catenin signaling in TNBC MDA-MB-231, MDA-MB-468 and Hs578T cells. Moreover, depletion of beta-catenin by shRNA sensitized TNBC cells to IR, whereas treatment of Wnt3a protein or overexpression of beta-catenin resulted in radioresistance of TNBC cells. Niclosamide, a potent inhibitor of Wnt/beta-catenin signaling, not only inhibited constitutive Wnt/beta-catenin signaling, but also blocked IR-induced Wnt/beta-catenin signaling in TNBC cells. In addition, niclosamide sensitized TNBC cells to IR, prevented Wnt3a-induced radioresistance, and overcame beta-catenin-induced radioresistance in TNBC cells. Importantly, animals treated with the combination of niclosamide and eta-ray local tumor irradiation had significant inhibition of MDA-MB-231 tumor growth compared with treated with local tumor irradiation alone. These findings indicate that Wnt/beta-catenin signaling pathway plays an important role in the development of radioresistance of TNBC cells, and that niclosamide had significant radiosensitizing effects by inhibiting Wnt/beta-catenin signaling in TNBC cells. Our study also provides rationale for further preclinical and clinical evaluation of niclosamide in TNBC management.