Nature Communications (Jun 2023)
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,
- Jordan M. Winter
Affiliations
- Ali Vaziri-Gohar
- Case Comprehensive Cancer Center, Case Western Reserve University
- Jonathan J. Hue
- Department of Surgery, Division of Surgical Oncology, University Hospitals, Cleveland Medical Center
- Ata Abbas
- Case Comprehensive Cancer Center, Case Western Reserve University
- Hallie J. Graor
- Case Comprehensive Cancer Center, Case Western Reserve University
- Omid Hajihassani
- Case Comprehensive Cancer Center, Case Western Reserve University
- Mehrdad Zarei
- Case Comprehensive Cancer Center, Case Western Reserve University
- George Titomihelakis
- Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University
- John Feczko
- Department of Genetics and Genome Sciences, Case Western Reserve University
- Moeez Rathore
- Case Comprehensive Cancer Center, Case Western Reserve University
- Sylwia Chelstowska
- Case Comprehensive Cancer Center, Case Western Reserve University
- Alexander W. Loftus
- Department of Surgery, Division of Surgical Oncology, University Hospitals, Cleveland Medical Center
- Rui Wang
- Case Comprehensive Cancer Center, Case Western Reserve University
- Mahsa Zarei
- Department of Veterinary Physiology and Pharmacology, Texas A&M University
- Maryam Goudarzi
- Proteomics and Metabolomics Core, Cleveland Clinic
- Renliang Zhang
- Proteomics and Metabolomics Core, Cleveland Clinic
- Belinda Willard
- Proteomics and Metabolomics Core, Cleveland Clinic
- Li Zhang
- Department of Molecular and Integrative Physiology, University of Michigan School of Medicine
- Adam Kresak
- Case Comprehensive Cancer Center, Case Western Reserve University
- Joseph E. Willis
- Department of Pathology, Case Western Reserve University and Department of Pathology Cleveland Medical Center
- Gi-Ming Wang
- Department of Population and Quantitative Health Sciences, Case Western Reserve University
- Curtis Tatsuoka
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh
- Joseph M. Salvino
- Molecular and Cellular Oncogenesis Program, The Wistar Institute
- Ilya Bederman
- Department of Genetics and Genome Sciences, Case Western Reserve University
- Henri Brunengraber
- Department of Nutrition and Biochemistry, Case Western Reserve University
- Costas A. Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan School of Medicine
- Jonathan R. Brody
- Brenden Colson Center for Pancreatic Care; Departments of Surgery and Cell, Developmental & Cancer Biology; Knight Cancer Institute, Oregon Health and Science University
- Jordan M. Winter
- Case Comprehensive Cancer Center, Case Western Reserve University
- DOI
- https://doi.org/10.1038/s41467-023-38921-8
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
