Lu Haiquan, Samanta Debangshu, Xiang Lisha, Zhang Huimin, Hu Hongxia, Chen Ivan, Bullen John W, Semenza Gregg L
Johns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Johns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):E4600-9. doi: 10.1073/pnas.1513433112. Epub 2015 Jul 30.
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 mitogen-activated 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.
三阴性乳腺癌（TNBC）占所有乳腺癌的10%-15%，但因其侵袭性特征和缺乏靶向治疗，在发病率和死亡率中所占比例过高。化疗会诱导乳腺癌干细胞（BCSCs）富集，而这些细胞会导致肿瘤复发和转移。在此，我们证明化疗以缺氧诱导因子（HIF）-1依赖的方式诱导胱氨酸转运蛋白xCT和谷氨酸-半胱氨酸连接酶（GCLM）调节亚基的表达，导致细胞内谷胱甘肽水平升高，后者通过铜螯合抑制丝裂原活化蛋白激酶激酶（MEK）活性。MEK-ERK信号通路的缺失导致FoxO3核转位以及多能性因子Nanog编码基因的转录激活，而Nanog是BCSCs富集所必需的。抑制xCT、GCLM、FoxO3或Nanog可阻断化疗诱导的BCSCs富集并损害肿瘤起始。这些结果表明，与化疗联合使用时，通过抑制HIF-1调节的谷胱甘肽合成来靶向BCSCs可能会改善TNBC的治疗效果。
