Gene/Protein
Disease
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Compound
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Gene/Protein
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Target Concepts:
Gene/Protein
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Query: EC:2.7.13.3 (
histidine kinase
)
2,405
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Neoplastic tissue exhibits high glucose utilization and over-expression of glucose transporters (GLUTs) and hexokinases (HKs), which can be imaged by (18)F-Fluorodeoxyglucose-positron emission tomography (FDG-PET). The aim of the present study was to investigate the expression of glycolysis-associated genes and to compare this with
FDG
-PET imaging as well as with the cellular proliferation index in two cancer entities with different malignant potential. Using real-time PCR, gene expression of GLUT1,
HK1
and HK2 were studied in 34 neuroendocrine tumors (NETs) in comparison with 14 colorectal adenocarcinomas (CRAs). The Ki67 proliferation index and, when available,
FDG
-PET imaging was compared with gene expression. Overexpression of GLUT1 gene expression was less frequent in NETs (38%) compared to CRAs (86%), P = 0.004.
HK1
was overexpressed in 41% and 71% of NETs and CRAs, respectively (P = 0.111) and HK2 was overexpressed in 50% and 64% of NETs and CRAs, respectively (P = 0.53). There was a significant correlation between the Ki67 proliferation index and GLUT1 gene expression for the NETs (R = 0.34, P = 0.047), but no correlation with the hexokinases.
FDG
-PET identified foci in significantly fewer NETs (36%) than CRAs (86%), (P = 0.04). The gene expression results, with less frequent GLUT1 and
HK1
upregulation in NETs, confirmed the lower metabolic activity of NETs compared to the more aggressive CRAs. In accordance with this, fewer NETs were
FDG
-PET positive compared to CRA tumors and
FDG
uptake correlated with GLUT1 gene expression.
...
PMID:Gene Expression of Glucose Transporter 1 (GLUT1), Hexokinase 1 and Hexokinase 2 in Gastroenteropancreatic Neuroendocrine Tumors: Correlation with F-18-fluorodeoxyglucose Positron Emission Tomography and Cellular Proliferation. 2682 29
Although absent in most adult tissues, hexokinase 2 (HK2) is expressed in a majority of tumors and contributes to increased glucose consumption and to in vivo tumor
18
F-
FDG
PET signaling.
Methods:
Both HK2 knockdown and knockout approaches were used to investigate the role of HK2 in cancer cell proliferation, in vivo xenograft tumor progression and
18
F-
FDG
tumor accumulation. BioProfiler analysis monitored cell culture glucose consumption and lactate production;
18
F-
FDG
PET/CT monitored in vivo tumor glucose accumulation. Cancer Cell Line Encyclopedia data were analyzed for
HK1
and HK2 expression.
Results:
Neither cell proliferation in culture nor xenograft tumor progression are inhibited by HK2 knockdown or knockout in cancer cells that express
HK1
and HK2. However, cancer subsets from a variety of tissues of origin express only HK2, but not
HK1
. In contrast to HK1+HK2+ cancers, HK2 knockdown in
HK1
-HK2+ cancer cells results in inhibition of cell proliferation, colony formation and xenograft tumor progression. Moreover, HK1KOHK2+ cancer cells are susceptible to HK2 inhibition, in contrast to their isogenic HK1+HK2+ parental cells.
Conclusion:
HK1
and HK2 expression are redundant in tumors; either can provide sufficient aerobic glycolysis for tumor growth; despite a reduction in
18
F-
FDG
PET signal. Therapeutic HK2 inhibition is likely to be restricted to
HK1
-HK2+ tumor subsets, but stratification of tumors that express HK2, but not
HK1
, should identify tumors treatable with emerging HK2 specific inhibitors.
...
PMID:Hexokinase 2 is targetable for HK1 negative, HK2 positive tumors from a wide variety of tissues of origin. 2988 May 5
Although the incidence of de novo neuroendocrine prostate cancer (PC) is rare, recent data suggest that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine hallmarks and androgen receptor (AR) suppression in PC. Previous clinical reports indicate that PCs with a phenotype similar to neuroendocrine tumors can be more amenable to imaging by
18
F-
FDG
than by PSMA-targeting radioligands. In this study, we evaluated the association between neuroendocrine gene signature and
18
F-
FDG
uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported
18
F-
FDG
avidity of PSMA-suppressed tumors.
Methods:
Data-mining approaches, cell lines, and patient-derived xenograft models were used to study the levels of 14 members of the
SLC2A
family (encoding GLUT proteins), 4 members of the hexokinase family (genes
HK1
-
HK3
and
GCK
), and PSMA (
FOLH1
gene) after AR inhibition and in correlation with neuroendocrine hallmarks. Also, we characterize a neuroendocrine-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no neuroendocrine histopathology. We measured glucose uptake in a neuroendocrine-induced in vitro model and a zebrafish model by nonradioactive imaging of glucose uptake using a fluorescent glucose bioprobe, GB2-Cy3.
Results:
This work demonstrated that a neuroendocrine gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of
GCK
(encoding glucokinase protein) and decreased expression of
SLC2A12
correlated with earlier biochemical recurrence. In tumors treated with AR inhibitors, high expression of
GCK
and low expression of
SLC2A12
correlated with neuroendocrine histopathology and PSMA gene suppression. GLUT12 suppression and upregulation of glucokinase were observed in neuroendocrine-induced PC cell lines and patient-derived xenograft models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model.
Conclusion:
A neuroendocrine gene signature in neuroendocrine PC and NELPC associates with a distinct transcriptional profile of GLUTs and hexokinases. PSMA suppression correlates with GLUT12 suppression and glucokinase upregulation. Alteration of
18
F-
FDG
uptake-associated genes correlated positively with higher glucose uptake in AR- and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient preclinical method for monitoring nonradioactive glucose uptake.
...
PMID:Differential Expression of Glucose Transporters and Hexokinases in Prostate Cancer with a Neuroendocrine Gene Signature: A Mechanistic Perspective for
18
F-FDG Imaging of PSMA-Suppressed Tumors. 3180 71
