Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

Haiquan Lu, Debangshu Samanta, Lisha Xiang, Huimin Zhang, Hongxia Hu, Ivan Chen, John W. Bullen, Gregg L. Semenza

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E4600-E4609
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number33
DOIs
StatePublished - Aug 18 2015

Keywords

  • Chemotherapy resistance
  • Hypoxia-inducible factor
  • Paclitaxel
  • Pluripotency factors
  • Tumor-initiating cells

ASJC Scopus subject areas

  • General

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