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Pharmacologic ascorbate (P-AscH−) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma

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Abstract

HIF-1α is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH−), induces cytotoxicity and oxidative stress selectively in cancer cells by acting as a pro-drug for the delivery of hydrogen peroxide (H2O2); early clinical data suggest improved survival and inhibition of metastasis in patients being actively treated with P-AscH−. Previous studies have demonstrated that activation of HIF-1α is necessary for P-AscH− sensitivity. We hypothesized that pancreatic cancer (PDAC) progression and metastasis could be be targeted by P-AscH− via H2O2-mediated inhibition of HIF-1α stabilization. Our study demonstrates an oxygen- and prolyl hydroxylase-independent regulation of HIF-1α by P-AscH−. Additionally, P-AscH− decreased VEGF secretion in a dose-dependent manner that was reversible with catalase, consistent with an H2O2-mediated mechanism. Pharmacological and genetic manipulations of HIF-1α did not alter P-AscH−-induced cytotoxicity. In vivo, P-AscH− inhibited tumor growth and VEGF expression. We conclude that P-AscH− suppresses the levels of HIF-1α protein in hypoxic conditions through a post-translational mechanism. These findings suggest potential new therapies specifically designed to inhibit the mechanisms that drive metastases as a part of PDAC treatment.

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Acknowledgements

HIF-1α Adenovirus construct obtained from Patrick H Maxwell, FMedSciRegius Professor of Physic & Head of the School of Clinical Medicine, University of Cambridge. Supported by NIH Grants CA184051, CA148062, CA169046, CA086862, and a Merit Review grant from the Medical Research Service, Department of Veterans Affairs 1I01BX001318-01A2.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    Justin G. Wilkes, Brianne R. O’Leary, Juan Du, Adrienne R. Klinger, Zita A. Sibenaller, Claire M. Doskey, Matthew S. Alexander, Garry R. Buettner & Joseph J. Cullen

  2. Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    Justin G. Wilkes, Brianne R. O’Leary, Juan Du, Matthew S. Alexander & Joseph J. Cullen

  3. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    Katherine N. Gibson-Corley

  4. Holden Comprehensive Cancer Center, Iowa City, IA, USA

    Katherine N. Gibson-Corley, Garry R. Buettner & Joseph J. Cullen

  5. The Medical College of Wisconsin, Milwaukee, WI, USA

    Susan Tsai

  6. Veterans Affairs Medical Center, Iowa City, IA, USA

    Joseph J. Cullen

  7. University of Iowa Hospitals and Clinics, 1528 JCP, 200 Hawkins Drive, Iowa City, IA, 52242, USA

    Joseph J. Cullen

Authors
  1. Justin G. Wilkes
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  2. Brianne R. O’Leary
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  3. Juan Du
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  7. Katherine N. Gibson-Corley
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  8. Matthew S. Alexander
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  11. Joseph J. Cullen
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Contributions

JC and JW conceived the hypothesis, designed the study, and performed the majority of the experiments. JW, BO, JD and KGC, performed experiments. JW, JC, and BO wrote the manuscript. JD, ZS, AK, KGC, and ST contributed reagents and tools for the study. JW, BO, GB, and JC contributed to discussion and edited the manuscript. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Joseph J. Cullen.

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Wilkes, J.G., O’Leary, B.R., Du, J. et al. Pharmacologic ascorbate (P-AscH−) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma. Clin Exp Metastasis 35, 37–51 (2018). https://doi.org/10.1007/s10585-018-9876-z

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