Increased glucose availability sensitizes pancreatic cancer to chemotherapy

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, Rui Wang, Mahsa Zarei, Maryam Goudarzi, Renliang Zhang, Belinda Willard, Li Zhang, Adam Kresak, Joseph E. Willis, Gi-Ming Wang, Curtis Tatsuoka, Joseph M. Salvino, Ilya Bederman, Henri Brunengraber, Costas A. Lyssiotis, Jonathan R. Brody and Jordan M. Winter ()
Additional contact information
Ali Vaziri-Gohar: Case Western Reserve University
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
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
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

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38921-8

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