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

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 WangCurtis Tatsuoka, Joseph M. Salvino, Ilya Bederman, Henri Brunengraber, Costas A. Lyssiotis, Jonathan R. Brody, Jordan M. Winter

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6 Scopus citations

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.

Original language	English (US)
Article number	3823
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-38921-8
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-023-38921-8

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Vaziri-Gohar, A., Hue, J. J., Abbas, A., Graor, H. J., Hajihassani, O., Zarei, M., Titomihelakis, G., Feczko, J., Rathore, M., Chelstowska, S., Loftus, A. W., Wang, R., Zarei, M., Goudarzi, M., Zhang, R., Willard, B., Zhang, L., Kresak, A., Willis, J. E., ... Winter, J. M. (2023). Increased glucose availability sensitizes pancreatic cancer to chemotherapy. Nature communications, 14(1), Article 3823. https://doi.org/10.1038/s41467-023-38921-8

Vaziri-Gohar, A, Hue, JJ, Abbas, A, Graor, HJ, Hajihassani, O, Zarei, M, Titomihelakis, G, Feczko, J, Rathore, M, Chelstowska, S, Loftus, AW, Wang, R, Zarei, M, Goudarzi, M, Zhang, R, Willard, B, Zhang, L, Kresak, A, Willis, JE, Wang, GM, Tatsuoka, C, Salvino, JM, Bederman, I, Brunengraber, H, Lyssiotis, CA, Brody, JR & Winter, JM 2023, 'Increased glucose availability sensitizes pancreatic cancer to chemotherapy', Nature communications, vol. 14, no. 1, 3823. https://doi.org/10.1038/s41467-023-38921-8

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title = "Increased glucose availability sensitizes pancreatic cancer to chemotherapy",

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.",

author = "Ali Vaziri-Gohar and Hue, {Jonathan J.} and Ata Abbas and Graor, {Hallie J.} and Omid Hajihassani and Mehrdad Zarei and George Titomihelakis and John Feczko and Moeez Rathore and Sylwia Chelstowska and Loftus, {Alexander W.} and Rui Wang and Mahsa Zarei and Maryam Goudarzi and Renliang Zhang and Belinda Willard and Li Zhang and Adam Kresak and Willis, {Joseph E.} and Wang, {Gi Ming} and Curtis Tatsuoka and Salvino, {Joseph M.} and Ilya Bederman and Henri Brunengraber and Lyssiotis, {Costas A.} and Brody, {Jonathan R.} and Winter, {Jordan M.}",

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doi = "10.1038/s41467-023-38921-8",

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AU - Vaziri-Gohar, Ali

AU - Hue, Jonathan J.

AU - Abbas, Ata

AU - Graor, Hallie J.

AU - Hajihassani, Omid

AU - Zarei, Mehrdad

AU - Titomihelakis, George

AU - Feczko, John

AU - Rathore, Moeez

AU - Chelstowska, Sylwia

AU - Loftus, Alexander W.

AU - Wang, Rui

AU - Zarei, Mahsa

AU - Goudarzi, Maryam

AU - Zhang, Renliang

AU - Willard, Belinda

AU - Zhang, Li

AU - Kresak, Adam

AU - Willis, Joseph E.

AU - Wang, Gi Ming

AU - Tatsuoka, Curtis

AU - Salvino, Joseph M.

AU - Bederman, Ilya

AU - Brunengraber, Henri

AU - Lyssiotis, Costas A.

AU - Brody, Jonathan R.

AU - Winter, Jordan M.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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Increased glucose availability sensitizes pancreatic cancer to chemotherapy

Abstract

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