PMID- 27132509
OWN - NLM
STAT- MEDLINE
DCOM- 20170906
LR  - 20180508
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 35
IP  - 47
DP  - 2016 Nov 24
TI  - A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis
      in EML4-ALK-positive lung cancer.
PG  - 6132-6142
LID - 10.1038/onc.2016.150 [doi]
AB  - A high rate of aerobic glycolysis is a hallmark of malignant transformation.
      Accumulating evidence suggests that diverse regulatory mechanisms mediate this
      cancer-associated metabolic change seen in a wide spectrum of cancer. The
      echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase
      (EML4-ALK) fusion protein is found in approximately 3-7% of non-small cell lung
      carcinomas (NSCLC). Molecular evidence and therapeutic effectiveness of
      FDA-approved ALK inhibitors indicated that EML4-ALK is a driving factor of lung
      tumorigenesis. A recent clinical study showed that NSCLC harboring EML4-ALK
      rearrangements displayed higher glucose metabolism compared with
      EML4-ALK-negative NSCLC. In the current work, we presented evidence that EML4-ALK
      is coupled to overexpression of hexokinase II (HK2), one of the rate-limiting
      enzymes of the glycolytic pathway. The link from EML4-ALK to HK2 upregulation is 
      essential for a high rate of glycolysis and proliferation of EML4-ALK-rearranged 
      NSCLC cells. We identified hypoxia-inducible factor 1alpha (HIF1alpha) as a key
      transcription factor to drive HK2 gene expression in normoxia in these cells.
      EML4-ALK induced hypoxia-independent but glucose-dependent accumulation of
      HIF1alpha protein via both transcriptional activation of HIF1alpha mRNA and the
      phosphatidylinositol 3 kinase-AKT pathway to enhance HIF1alpha protein synthesis.
      The EML4-ALK-mediated upregulation of HIF1alpha, HK2 and glycolytic metabolism
      was also highly active in vivo as demonstrated by fluorodeoxyglucose-positron
      emission tomography imaging of xenografts grown from EML4-ALK-positive NSCLC
      cells. Our data reveal a novel EML4-ALK-HIF1alpha-HK2 cascade to enhance glucose 
      metabolism in EML4-ALK-positive NSCLC.
FAU - Ma, Y
AU  - Ma Y
AD  - Department of Biochemistry and Molecular Biology, Virginia Commonwealth
      University School of Medicine, Richmond, VA, USA.
FAU - Yu, C
AU  - Yu C
AD  - College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
FAU - Mohamed, E M
AU  - Mohamed EM
AD  - Department of Biochemistry and Molecular Biology, Virginia Commonwealth
      University School of Medicine, Richmond, VA, USA.
FAU - Shao, H
AU  - Shao H
AD  - Department of Biochemistry and Molecular Biology, Virginia Commonwealth
      University School of Medicine, Richmond, VA, USA.
FAU - Wang, L
AU  - Wang L
AD  - Department of Radiology, Virginia Commonwealth University School of Medicine,
      Richmond, VA, USA.
FAU - Sundaresan, G
AU  - Sundaresan G
AD  - Department of Radiology, Virginia Commonwealth University School of Medicine,
      Richmond, VA, USA.
FAU - Zweit, J
AU  - Zweit J
AD  - Department of Radiology, Virginia Commonwealth University School of Medicine,
      Richmond, VA, USA.
FAU - Idowu, M
AU  - Idowu M
AD  - Department of Pathology, Virginia Commonwealth University School of Medicine,
      Richmond, VA, USA.
FAU - Fang, X
AU  - Fang X
AD  - Department of Biochemistry and Molecular Biology, Virginia Commonwealth
      University School of Medicine, Richmond, VA, USA.
LA  - eng
GR  - P30 CA016059/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160502
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (EML4-ALK fusion protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.1 (Hexokinase)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (anaplastic lymphoma kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - *Gene Expression Regulation, Enzymologic
MH  - *Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Glucose/metabolism
MH  - Glycolysis
MH  - Heterografts
MH  - Hexokinase/*genetics/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Lung Neoplasms/diagnostic imaging/*genetics/*metabolism/pathology
MH  - Mice
MH  - Oncogene Proteins, Fusion/*genetics/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA, Small Interfering
MH  - Receptor Protein-Tyrosine Kinases/*genetics/metabolism
MH  - Signal Transduction
MH  - Transcriptional Activation
PMC - PMC5093092
MID - NIHMS772960
EDAT- 2016/05/03 06:00
MHDA- 2017/09/07 06:00
CRDT- 2016/05/03 06:00
PHST- 2015/10/29 00:00 [received]
PHST- 2016/03/05 00:00 [revised]
PHST- 2016/03/24 00:00 [accepted]
PHST- 2016/05/03 06:00 [pubmed]
PHST- 2017/09/07 06:00 [medline]
PHST- 2016/05/03 06:00 [entrez]
AID - onc2016150 [pii]
AID - 10.1038/onc.2016.150 [doi]
PST - ppublish
SO  - Oncogene. 2016 Nov 24;35(47):6132-6142. doi: 10.1038/onc.2016.150. Epub 2016 May 
      2.