Journal article
Pharmacologic ascorbate (P-AscH - ) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma
Clinical & experimental metastasis, Vol.35(1-2), pp.37-51
02/2018
DOI: 10.1007/s10585-018-9876-z
PMCID: PMC5959274
PMID: 29396728
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 (H
O
); 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 H
O
-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 H
O
-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.
Details
- Title: Subtitle
- Pharmacologic ascorbate (P-AscH - ) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma
- Creators
- Justin G Wilkes - Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USABrianne R O'Leary - Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USAJuan Du - Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USAAdrienne R Klinger - Department of Radiation Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USAZita A Sibenaller - Department of Radiation Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USAClaire M Doskey - Department of Radiation Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USAKatherine N Gibson-Corley - Holden Comprehensive Cancer Center, Iowa City, IA, USAMatthew S Alexander - Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USASusan Tsai - The Medical College of Wisconsin, Milwaukee, WI, USAGarry R Buettner - Holden Comprehensive Cancer Center, Iowa City, IA, USAJoseph J Cullen - University of Iowa Hospitals and Clinics, 1528 JCP, 200 Hawkins Drive, Iowa City, IA, 52242, USA. joseph-cullen@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Clinical & experimental metastasis, Vol.35(1-2), pp.37-51
- DOI
- 10.1007/s10585-018-9876-z
- PMID
- 29396728
- PMCID
- PMC5959274
- NLM abbreviation
- Clin Exp Metastasis
- ISSN
- 0262-0898
- eISSN
- 1573-7276
- Publisher
- Netherlands
- Grant note
- CA148062 / National Institutes of Health P30 ES005605 / NIEHS NIH HHS CA086862 / National Institutes of Health T32 CA078586 / NCI NIH HHS T32 CA148062 / NCI NIH HHS CA169046 / National Institutes of Health I01 BX001318 / BLRD VA 1I01BX001318-01A2 / U.S. Department of Veterans Affairs R01 CA184051 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA169046 / NCI NIH HHS CA18451 / National Institutes of Health
- Language
- English
- Date published
- 02/2018
- Academic Unit
- Pathology; Surgery; Radiation Oncology; Ophthalmology and Visual Sciences
- Record Identifier
- 9984047797902771
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