Document Type
Article
Publication Date
6-28-2023
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.
Recommended Citation
Vaziri-Gohar, Ali; Hue, Jonathan J.; Abbas, Ata; Graor, Hallie J.; Hajihassani, Omid; Zarei, Mehrdad; Titomihelakis, George; Feczko, John; Rathore, Moeez; Chelstowska, Sylwia; Loftus, Alexander W.; Wang, Rui; Zarei, Mahsa; Goudarzi, Maryam; Zhang, Renliang; Willard, Belinda; Zhang, Li; Kresak, Adam; Willis, Joseph E.; Wang, Gi-Ming; Tatsuoka, Curtis; Salvino, Joseph M.; Bederman, Ilya; Brunengraber, Henri; Lyssiotis, Costas A.; Brody, Jonathan R.; and Winter, Jordan M., "Increased Glucose Availability Sensitizes Pancreatic Cancer to Chemotherapy" (2023). Student Papers, Posters & Projects. Paper 110.
https://jdc.jefferson.edu/student_papers/110
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Supplementary Information
Peer Review File.pdf (2684 kB)
41467_2023_38921_MOESM3_ESM.pdf (1611 kB)
Reporting Summary
Language
English
Comments
This article is the author's final published version in Nature Communications, Volume 14, 2023, Article number 3823.
The published version is available at https://doi.org/10.1038/s41467-023-38921-8. Copyright © The Author(s) 2023.