title: Ablation of CD44 induces glycolysis-to-oxidative phosphorylation transition via modulation of the c-Src-Akt-LKB1-AMPKα pathway.
abstract: 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.
authors.affiliation: Department of Life Science, Hanyang University, Seoul 133-791, Korea.
authors.forename: KeeSoo
authors.initials: K
authors.lastname: Nam
authors.affiliation: Department of Life Science, Hanyang University, Seoul 133-791, Korea.
authors.forename: Sunhwa
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Life Science, Hanyang University, Seoul 133-791, Korea Natural Science Institute, Hanyang University, Seoul 133-791, Korea.
authors.forename: Incheol
authors.initials: I
authors.lastname: Shin
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D045744:Cell Line, Tumor; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D010085:Oxidative Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: C497483:CD44 protein, human; C497442:HIF1A protein, human; D018960:Hyaluronan Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007773:Lactates; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D016392:Proto-Oncogene Proteins pp60(c-src); D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; CD44; LDHA; LDHB; c-Src