RETRACTED: PHGDH Expression Is Required for Mitochondrial Redox Homeostasis, Breast Cancer Stem Cell Maintenance, and Lung Metastasis.
Intratumoral hypoxia stimulates enrichment of breast cancer stem cells (BCSC), which are critical for metastasis and patient mortality. Here we report a metabolic adaptation that is required for hypoxia-induced BCSC enrichment and metastasis. Hypoxia-inducible factors coordinately regulate expression of genes encoding phosphoglycerate dehydrogenase (PHGDH) and five downstream enzymes in the serine synthesis pathway and mitochondrial one-carbon (folate) cycle. RNAi-mediated silencing of PHGDH expression in both estrogen receptor-positive and negative breast cancer cells led to decreased NADPH levels, disturbed mitochondrial redox homeostasis, and increased apoptosis, which abrogated BCSC enrichment under hypoxic conditions. PHGDH-deficient cells exhibited increased oxidant levels and apoptosis, as well as loss of BCSC enrichment, in response to treatment with carboplatin or doxorubicin. PHGDH-deficient cells were relatively weakly tumorigenic and tumors that did form were deficient in BCSCs, abolishing metastatic capacity. Our findings highlight a role for PHGDH in the formation of secondary (recurrent or metastatic) tumors, with potential implications for therapeutic targeting of advanced cancers. Cancer Res; 76(15); 4430-42. ©2016 AACR.
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Debangshu
D
Samanta
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Youngrok
Y
Park
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Shaida A
SA
Andrabi
Human Metabolome Technologies America, Inc., Boston, Massachusetts.
Laura M
LM
Shelton
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Daniele M
DM
Gilkes
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Departments of Pediatrics, Medicine, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland. gsemenza@jhmi.edu.
Gregg L
GL
Semenza
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D008928:Mitochondria / Q000378:metabolism*; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050543:Phosphoglycerate Dehydrogenase / Q000378:metabolism*; D014162:Transfection
D050543:Phosphoglycerate Dehydrogenase