Increased glucose availability sensitizes pancreatic cancer to chemotherapy

• Published in: Nature communications Vol. 14; no. 1; pp. 3823 - 13
• Main Authors: 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., Winter, Jordan M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 38; 38/91; 631/67/1059; 631/67/2327; 631/67/327; Adenocarcinoma; Administration, Cutaneous; Animal models; Animals; Anticancer properties; Availability; Biosynthesis; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Chemotherapy; Effectiveness; Glucose; Glutamate-cysteine ligase; Glutathione; Humanities and Social Sciences; Hyperglycemia; Mice; Multiagent systems; multidisciplinary; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Science; Science (multidisciplinary); Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38921-8

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. Response to chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC) is often limited. Here, the authors report improved response to chemotherapy in PDAC patients with hyperglycaemia and investigate the underlying mechanism via glucose-mediated disruption of redox metabolism