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Cited by 525Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancer

Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin

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DeWaal, Dannielle, Nogueira, Veronique, Terry, Alexander R., Patra, Krushna C., Jeon, Sang-Min, Guzman, Grace, Au, Jennifer, Long, Christopher P. +2 more·2018·Nature Communications
DOI 10.1038/s41467-017-02733-4PMC PMC5792493
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Abstract

Hepatocellular carcinoma (HCC) cells are metabolically distinct from normal hepatocytes by expressing the high-affinity hexokinase (HK2) and suppressing glucokinase (GCK). This is exploited to selectively target HCC. Hepatic HK2 deletion inhibits tumor incidence in a mouse model of hepatocarcinogenesis. Silencing HK2 in human HCC cells inhibits tumorigenesis and increases cell death, which cannot be restored by GCK or mitochondrial binding deficient HK2. Upon HK2 silencing, glucose flux to pyruvate and lactate is inhibited, but TCA fluxes are maintained. Serine uptake and glycine secretion are elevated suggesting increased requirement for one-carbon contribution. Consistently, vulnerability to serine depletion increases. The decrease in glycolysis is coupled to elevated oxidative phosphorylation, which is diminished by metformin, further increasing cell death and inhibiting tumor growth. Neither HK2 silencing nor metformin alone inhibits mTORC1, but their combination inhibits mTORC1 in an AMPK-independent and REDD1-dependent mechanism. Finally, HK2 silencing synergizes with sorafenib to inhibit tumor growth.

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  • HepG2 expresses high-affinity hexokinase II (HK2) instead of glucokinase (GCK), maintaining high glycolysis even at low glucose.

    “While mature hepatocytes express glucokinase (GCK, hexokinase IV), whose activity is regulated by physiological glucose concentrations and insulin, GCK expression is suppressed in HepG2 cells, which produce high-affinity hexokinase II (HK2) [116,117,118].”

    From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [117]

    The Introduction says GCK is the major hexokinase in normal differentiated hepatocytes, whereas GCK is repressed and HK2 induced in HCC; it also identifies HK2 as high-affinity. The Results show that HK2 loss reduces glycolytic function in HepG2 cells. Our copy does not establish that HepG2 maintains high glycolysis at low glucose or state that insulin regulates GCK activity. (LLM, conf=0.84)

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Research works printed but not linked: 30

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Cited by

Sorted by citations

Authors
DeWaal, D., Nogueira, V., Terry, A. R., Patra, K. C., Jeon, S.-M., Guzman, G., Au, J., Long, C. P., Antoniewicz, M. R., & Hay, N.
Affiliations
  • University of Illinois Chicago (US)
  • Harvard University (US)
  • University of Delaware (US)
Corresponding author
  • Antoniewicz, Maciek R.
  • Hay, Nissim
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-01-31
Volume
9
Issue
1
Pages
446-446
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-02733-4
PMC
PMC5792493
OpenAlex
W2801000404
Cited by
525
References
1
Citations by year
2026: 45 · 2025: 69 · 2024: 66 · 2023: 63 · 2022: 89 · 2021: 72 · 2020: 66 · 2019: 32 · 2018: 20
FWCI
14.96
Type
journal article
Language
en
Update notices
correction (2018-06-26)
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX000733)
  • GlaxoSmithKline
  • National Institutes of Health (BX000733, CA090764)
  • National Institute on Aging (R01AG016927)
  • National Cancer Institute (R01CA206167, F30CA225058, R01CA090764)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
hexokinase 2, hepatocellular carcinoma, glycolysis, oxidative phosphorylation, metformin, serine metabolism, one-carbon metabolism, mTORC1, REDD1, glucose metabolism, cancer cell death, glucokinase
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Sorafenib, Animals, Antineoplastic Agents, Glycolysis, Carcinoma, Hepatocellular, Hexokinase, Humans, Hypoglycemic Agents, Liver Neoplasms, Male, Metformin, Mice, Nude, Niacinamide, Oxidative Phosphorylation, Phenylurea Compounds, Xenograft Model Antitumor Assays, Hep G2 Cells, Molecular Targeted Therapy, Carcinogenesis, Metabolic Flux Analysis

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