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

doi:10.1038/s41467-023-38921-8

Increased glucose availability sensitizes pancreatic cancer to chemotherapy

Nat Commun. 2023 Jun 28;14(1):3823. doi: 10.1038/s41467-023-38921-8.

Authors

Ali Vaziri-Gohar^{1

2}, Jonathan J Hue³, Ata Abbas⁴, Hallie J Graor⁴, Omid Hajihassani⁴, Mehrdad Zarei^{4

3}, George Titomihelakis⁵, John Feczko⁶, Moeez Rathore⁴, Sylwia Chelstowska⁴, Alexander W Loftus³, Rui Wang⁴, Mahsa Zarei⁷, Maryam Goudarzi⁸, Renliang Zhang⁸, Belinda Willard⁸, Li Zhang⁹, Adam Kresak^{4

10}, Joseph E Willis¹⁰, Gi-Ming Wang¹¹, Curtis Tatsuoka¹², Joseph M Salvino¹³, Ilya Bederman⁶, Henri Brunengraber¹⁴, Costas A Lyssiotis⁹, Jonathan R Brody¹⁵, Jordan M Winter^{16

17}

Affiliations

¹ Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA. [email protected].
² Department of Cancer Biology, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA. [email protected].
³ Department of Surgery, Division of Surgical Oncology, University Hospitals, Cleveland Medical Center, Cleveland, OH, USA.
⁴ Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
⁵ Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
⁶ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁷ Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA.
⁸ Proteomics and Metabolomics Core, Cleveland Clinic, Cleveland, OH, USA.
⁹ Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
¹⁰ Department of Pathology, Case Western Reserve University and Department of Pathology Cleveland Medical Center, Cleveland, OH, USA.
¹¹ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
¹² Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
¹⁴ Department of Nutrition and Biochemistry, Case Western Reserve University, Cleveland, OH, USA.
¹⁵ Brenden Colson Center for Pancreatic Care; Departments of Surgery and Cell, Developmental & Cancer Biology; Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
¹⁶ Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA. [email protected].
¹⁷ Department of Surgery, Division of Surgical Oncology, University Hospitals, Cleveland Medical Center, Cleveland, OH, USA. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Administration, Cutaneous
Animals
Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Glucose
Mice
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics

Substances

Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding