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Increased glucose availability sensitizes pancreatic cancer to chemotherapy

Author

Listed:
  • Ali Vaziri-Gohar

    (Case Western Reserve University
    Loyola University Chicago)

  • Jonathan J. Hue

    (University Hospitals, Cleveland Medical Center)

  • Ata Abbas

    (Case Western Reserve University)

  • Hallie J. Graor

    (Case Western Reserve University)

  • Omid Hajihassani

    (Case Western Reserve University)

  • Mehrdad Zarei

    (Case Western Reserve University
    University Hospitals, Cleveland Medical Center)

  • George Titomihelakis

    (Thomas Jefferson University)

  • John Feczko

    (Case Western Reserve University)

  • Moeez Rathore

    (Case Western Reserve University)

  • Sylwia Chelstowska

    (Case Western Reserve University)

  • Alexander W. Loftus

    (University Hospitals, Cleveland Medical Center)

  • Rui Wang

    (Case Western Reserve University)

  • Mahsa Zarei

    (Texas A&M University)

  • Maryam Goudarzi

    (Cleveland Clinic)

  • Renliang Zhang

    (Cleveland Clinic)

  • Belinda Willard

    (Cleveland Clinic)

  • Li Zhang

    (University of Michigan School of Medicine)

  • Adam Kresak

    (Case Western Reserve University
    Case Western Reserve University and Department of Pathology Cleveland Medical Center)

  • Joseph E. Willis

    (Case Western Reserve University and Department of Pathology Cleveland Medical Center)

  • Gi-Ming Wang

    (Case Western Reserve University)

  • Curtis Tatsuoka

    (University of Pittsburgh)

  • Joseph M. Salvino

    (The Wistar Institute)

  • Ilya Bederman

    (Case Western Reserve University)

  • Henri Brunengraber

    (Case Western Reserve University)

  • Costas A. Lyssiotis

    (University of Michigan School of Medicine)

  • Jonathan R. Brody

    (Oregon Health and Science University)

  • Jordan M. Winter

    (Case Western Reserve University
    University Hospitals, Cleveland Medical Center)

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.

Suggested Citation

  • Ali Vaziri-Gohar & Jonathan J. Hue & Ata Abbas & Hallie J. Graor & Omid Hajihassani & Mehrdad Zarei & George Titomihelakis & John Feczko & Moeez Rathore & Sylwia Chelstowska & Alexander W. Loftus & Ru, 2023. "Increased glucose availability sensitizes pancreatic cancer to chemotherapy," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38921-8
    DOI: 10.1038/s41467-023-38921-8
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    References listed on IDEAS

    as
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