Cluster of differentiation 44 (CD44) is a transmembrane glycoprotein that has been identified as a cancer stem cell marker in various cancer cells. Although many studies have focused on CD44 as a cancer stem cell marker, its effect on cancer cell metabolism remains unclear. To investigate the role of CD44 on cancer cell metabolism, we established CD44 knock-down cells via retroviral delivery of shRNA against CD44 in human breast cancer cells. Silencing of CD44 decreased the glycolytic phenotype of cancer cells, affecting glucose uptake, ATP production, and lactate production. We also found that ablation of the CD44-induced lactate dehydrogenase (LDH) isoenzyme results in a shift to LDH1 due to LDHA down-regulation and LDHB up-regulation, implying the importance of LDH isoenzyme modulation on cancer metabolism. The expression of glycolysis-related proteins including hypoxia inducible factor-1α (HIF-1α) and LDHA was decreased by CD44 silencing. These effects were due to the up-regulation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)α activity by reduction in c-Src and Akt activity in CD44 knock-down cells. Finally, induction of LKB1/AMPKα activity blocked the expression of HIF-1α and its target gene, LDHA. Inversely, LDHB expression was repressed by HIF-1α. Collectively, these results indicate that the CD44 silencing-induced metabolic shift is mediated by the regulation of c-Src/Akt/LKB1/AMPKα/HIF-1α signaling in human breast cancer cells.
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October 2016
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Cover Image
Cover Image
Crystal structure of human hemoglobin β subunit (PDB ID: 1A3N) with an in silico mutation of phenylalanine 41 to tyrosine (green) to enhance function as a blood substitute; image kindly provide by Brandon Reeder and Chris Cooper (University of Essex). For details see Silkstone et al. in this issue (pages 3371–3383).
Research Article|
September 27 2016
Ablation of CD44 induces glycolysis-to-oxidative phosphorylation transition via modulation of the c-Src–Akt–LKB1–AMPKα pathway
KeeSoo Nam;
KeeSoo Nam
1Department of Life Science, Hanyang University, Seoul 133-791, Korea
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Sunhwa Oh;
Sunhwa Oh
1Department of Life Science, Hanyang University, Seoul 133-791, Korea
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Incheol Shin
Incheol Shin
1Department of Life Science, Hanyang University, Seoul 133-791, Korea
2Natural Science Institute, Hanyang University, Seoul 133-791, Korea
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Publisher: Portland Press Ltd
Received:
June 27 2016
Revision Received:
July 22 2016
Accepted:
July 25 2016
Accepted Manuscript online:
July 25 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (19): 3013–3030.
Article history
Received:
June 27 2016
Revision Received:
July 22 2016
Accepted:
July 25 2016
Accepted Manuscript online:
July 25 2016
Citation
KeeSoo Nam, Sunhwa Oh, Incheol Shin; Ablation of CD44 induces glycolysis-to-oxidative phosphorylation transition via modulation of the c-Src–Akt–LKB1–AMPKα pathway. Biochem J 1 October 2016; 473 (19): 3013–3030. doi: https://doi.org/10.1042/BCJ20160613
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