Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype
Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype
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DOI：
10.1073/pnas.1513433112
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发表时间：
2015-08-18
影响因子：
11.1
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Lu, Haiquan;Samanta, Debangshu;Semenza, Gregg L.
三阴性乳腺癌（TNBC）占所有乳腺癌的10-15%，但由于其侵袭性特征和缺乏靶向治疗，导致发病率和死亡率不成比例。化疗诱导乳腺癌干细胞（BCSC）富集，这是肿瘤复发和转移的原因。在这里，我们证明，化疗诱导表达的胱氨酸转运蛋白xCT和谷氨酸-半胱氨酸连接酶（GCLM）的调节亚基在缺氧诱导因子（HIF）-1依赖的方式，导致细胞内谷胱甘肽水平增加，抑制丝裂原活化蛋白激酶激酶（MEK）的活性，通过铜螯合。MEK-ERK信号传导的丧失导致FoxO 3核转位和编码多能性因子Nanog的基因的转录激活，这是BCSC富集所需的。xCT、GCLM、FoxO 3或Nanog的抑制阻断化疗诱导的BCSC富集并损害肿瘤起始。这些结果表明，与化疗联合，通过抑制HIF-1调节的谷胱甘肽合成靶向BCSC可能会改善TNBC的结局。
Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogenactivated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy- induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC.