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

Author

Listed:
  • Dannielle DeWaal

    (University of Illinois at Chicago)

  • Veronique Nogueira

    (University of Illinois at Chicago)

  • Alexander R. Terry

    (University of Illinois at Chicago)

  • Krushna C. Patra

    (University of Illinois at Chicago
    Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Sang-Min Jeon

    (University of Illinois at Chicago
    Ajou University Yeongtong-gu)

  • Grace Guzman

    (University of Illinois Hospital and Health Science Chicago)

  • Jennifer Au

    (University of Delaware)

  • Christopher P. Long

    (University of Delaware)

  • Maciek R. Antoniewicz

    (University of Delaware)

  • Nissim Hay

    (University of Illinois at Chicago
    Jesse Brown VA Medical Center)

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.

Suggested Citation

  • Dannielle DeWaal & Veronique Nogueira & Alexander R. Terry & Krushna C. Patra & Sang-Min Jeon & Grace Guzman & Jennifer Au & Christopher P. Long & Maciek R. Antoniewicz & Nissim Hay, 2018. "Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02733-4
    DOI: 10.1038/s41467-017-02733-4
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    Cited by:

    1. Tuncer, Turker & Ertam, Fatih, 2020. "Neighborhood component analysis and reliefF based survival recognition methods for Hepatocellular carcinoma," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 540(C).
    2. Catherine S. Blaha & Gopalakrishnan Ramakrishnan & Sang-Min Jeon & Veronique Nogueira & Hyunsoo Rho & Soeun Kang & Prashanth Bhaskar & Alexander R. Terry & Alexandre F. Aissa & Maxim V. Frolov & Krush, 2022. "A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Emmanuel Benichou & Bolaji Seffou & Selin Topçu & Ophélie Renoult & Véronique Lenoir & Julien Planchais & Caroline Bonner & Catherine Postic & Carina Prip-Buus & Claire Pecqueur & Sandra Guilmeau & Ma, 2024. "The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism," Nature Communications, Nature, vol. 15(1), pages 1-29, December.

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