Journal
MOLECULAR CANCER RESEARCH
Volume 14, Issue 6, Pages 528-538Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-16-0050
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Funding
- Mary Kay Foundation
- National Institute of General Medical Sciences [U54GM104942]
- NIH [GM103488/RR032138, RR020866, OD016165, GM103434, P20 RR016440, P30 RR032138/GM103488, P20 RR016477]
- Mary Babb Randolph Cancer Center
- Cancer Research UK [18278] Funding Source: researchfish
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Resistance to anoikis is a prerequisite for tumor metastasis. The epithelial-to-mesenchymal transition (EMT) allows tumor cells to evade anoikis. The wound-healing regulatory transcription factor Grainyhead-like 2 (GRHL2) suppresses/reverses EMT, accompanied by suppression of the cancer stem cell (CSC) phenotype and by resensitization to anoikis. Here, the effects of GRHL2 upon intracellular metabolism in the context of reversion of the EMT/CSC phenotype, with a view toward understanding how these effects promote anoikis sensitivity, were investigated. EMT enhanced mitochondrial oxidative metabolism. Although this was accompanied by higher accumulation of superoxide, the overall level of reactive oxygen species (ROS) declined, due to decreased hydrogen peroxide. Glutamate dehydrogenase 1 (GLUD1) expression increased in EMT, and this increase, via the product alpha-ketoglutarate (alpha-KG), was important for suppressing hydrogen peroxide and protecting against anoikis. GRHL2 suppressed GLUD1 gene expression, decreased alpha-KG, increased ROS, and sensitized cells to anoikis. (C) 2016 AACR.
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