Neuromedin U alters bioenergetics and expands the cancer stem cell phenotype in HER2-positive breast cancer
Neuromedin U alters bioenergetics and expands the cancer stem cell phenotype in HER2-positive breast cancer
复制标题
Neuromedin U改变her2阳性乳腺癌的生物能量学并扩大癌症干细胞表型
DOI：
10.1002/ijc.30705
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发表时间：
2017-06-15
影响因子：
6.4
通讯作者：
O'Driscoll, Lorraine
中科院分区：
文献类型：
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作者：
Martinez, Vanesa G.;Crown, John;O'Driscoll, Lorraine
Neuromedin U (NmU) 是一种神经肽，属于神经调节肽家族。最近，我们报道了 NmU 与乳腺癌之间的显着关联，特别是与侵袭性增加、对 HER2 靶向治疗的耐药性以及患者总体预后显着较差相关，尽管其发挥这种作用的机制仍不清楚。通过研究，我们发现 HER2 阳性乳腺癌细胞中 NmU 的异位过度表达会诱导代谢异常，糖酵解增加，这可能是由于丙酮酸脱氢酶激酶活性增强所致。在针对 HER2 的耐药细胞变体中也观察到了类似的结果，我们之前已证明这些细胞变体的 NmU 水平有所增加。 NmU 的过度表达还导致上皮-间质转化标记物上调和 IL-6 分泌增加，再加上异常代谢，都与癌症干细胞 (CSC) 表型相关。流式细胞术实验证实，NmU过表达和HER2靶向耐药细胞显示出具有CSC表型（CD44（+）/CD24（-））的细胞比例增加。总而言之，我们的结果报告了 NmU 在 HER2 过表达乳腺癌中的新作用机制，通过赋予 CSC 特征和扩展 CSC 表型来增强对 HER2 靶向药物的耐药性。有什么新内容？癌细胞表现出各种代谢适应，这有助于肿瘤的侵袭性和耐药性，并且是干性的先决条件。然而，代谢异常与癌细胞干性之间的联系尚不完全清楚。在此，HER2 阳性乳腺癌细胞干性的增加与神经调节素 (NmU) 的过度表达有关，神经调节素是一种具有能量稳态功能的神经肽。异位和诱导的 NmU 过表达导致具有癌症干细胞 (CSC) 表型的细胞比例以及与 CSC 表型相关的关键标记物的比例增加。研究结果表明，NmU 可能是 HER2 阳性乳腺癌的一个有价值的治疗靶点。
Neuromedin U (NmU) is a neuropeptide belonging to the neuromedin family. Recently, we reported a significant association between NmU and breast cancer, particularly correlating with increased aggressiveness, resistance to HER2-targeted therapies and overall significantly poorer outcome for patients, although the mechanism through which it exerts this effect remained unexplained. Investigating this, here we found that ectopic over-expression of NmU in HER2-positive breast cancer cells induced aberrant metabolism, with increased glycolysis, likely due to enhanced pyruvate dehydrogenase kinase activity. Similar results were observed in HER2-targeted drug-resistant cell variants, which we had previously shown to display increased levels of NmU. Overexpression of NmU also resulted in upregulation of epithelial-mesenchymal transition markers and increased IL-6 secretion which, together with aberrant metabolism, have all been associated with the cancer stem cell (CSC) phenotype. Flow cytometry experiments confirmed that NmU-overexpressing and HER2-targeted drug-resistant cells showed an increased proportion of cells with CSC phenotype (CD44(+)/CD24(-)). Taken together, our results report a new mechanism of action for NmU in HER2-overexpressing breast cancer that enhances resistance to HER2-targeted drugs through conferring CSC characteristics and expansion of the CSC phenotype.What's new? Cancer cells exhibit various metabolic adaptations, which contribute to tumor aggressiveness and drug resistance and are a prerequisite for stemness. The link between metabolic abnormalities and stemness in cancer cells, however, is not fully understood. Here, increased stemness in HER2-positive breast cancer cells was associated with overexpression of neuromedin (NmU), a neuropeptide with functions in energy homeostasis. Ectopic and induced NmU overexpression resulted in increases in the proportion of cells with cancer stem cell (CSC) phenotypes and in key markers associated with CSC phenotype. The findings suggest that NmU could be a valuable therapeutic target in HER2-positive breast cancer.