Ablation of CD44 induces glycolysis-to-oxidative phosphorylation transition via modulation of the c-Src-Akt-LKB1-AMPK alpha pathway

Title
Ablation of CD44 induces glycolysis-to-oxidative phosphorylation transition via modulation of the c-Src-Akt-LKB1-AMPK alpha pathway
Author
신인철
Keywords
ACTIVATED PROTEIN-KINASE; INDUCIBLE FACTOR-I; LACTATE-DEHYDROGENASE-A; CANCER-CELLS; CYTOSKELETON ACTIVATION; METABOLIC CHECKPOINT; AEROBIC GLYCOLYSIS; RESPONSE ELEMENTS; UPSTREAM KINASE; PYRUVATE-KINASE
Issue Date
2016-10
Publisher
PORTLAND PRESS LTD
Citation
BIOCHEMICAL JOURNAL, v. 473, no. 19, Page. 3013-3030
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-1 alpha (HIF-1 alpha) 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) a activity by reduction in c-Src and Akt activity in CD44 knock-down cells. Finally, induction of LKB1/AMPK alpha activity blocked the expression of HIF-1 alpha and its target gene, LDHA. Inversely, LDHB expression was repressed by HIF-1 alpha. Collectively, these results indicate that the CD44 silencing-induced metabolic shift is mediated by the regulation of c-Src/Akt/LKB1/AMPK alpha/HIF-1 alpha signaling in human breast cancer cells.
URI
http://www.biochemj.org/content/473/19/3013http://repository.hanyang.ac.kr/handle/20.500.11754/99302
ISSN
0264-6021; 1470-8728
DOI
10.1042/BCJ20160613
Appears in Collections:
COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > LIFE SCIENCE(생명과학과) > Articles
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