Journal article
Pharmacological ascorbate induces sustained mitochondrial dysfunction
Free radical biology & medicine, Vol.204, pp.108-117
05/01/2023
DOI: 10.1016/j.freeradbiomed.2023.04.023
PMCID: PMC10375417
PMID: 37137343
Abstract
Pharmacological ascorbate (P-AscH-; high dose given intravenously) generates H2O2 that is selectively cytotoxic to cancer compared to normal cells. The RAS-RAF-ERK1/2 is a major signaling pathway in cancers carrying RAS mutations and is known to be activated by H2O2. Activated ERK1/2 also phosphorylates the GTPase dynamin-related protein (Drp1), which then stimulates mitochondrial fission. Although early generation of H2O2 leads to cytotoxicity of cancer cells, we hypothesized that sustained increases in H2O2 activate ERK-Drp1 signaling, leading to an adaptive response; inhibition of this pathway would enhance the toxicity of P-AscH-. Increases in phosphorylated ERK and Drp1 induced by P-AscH- were reversed with genetic and pharmacological inhibitors of ERK and Drp1, as well as in cells lacking functional mitochondria. P-AscH- increased Drp1 colocalization to mitochondria, decreased mitochondrial volume, increased disconnected components, and decreased mitochondrial length, suggesting an increase in mitochondrial fission 48 h after treatment with P-AscH-. P-AscH- decreased clonogenic survival; this was enhanced by genetic and pharmacological inhibition of both ERK and Drp1. In murine tumor xenografts, the combination of P-AscH- and pharmacological inhibition of Drp1 increased overall survival. These results suggest that P-AscH- induces sustained changes in mitochondria, through activation of the ERK/Drp1 signaling pathway, an adaptive response. Inhibition of this pathway enhanced the toxicity P-AscH- to cancer cells.
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•Increases in phosphorylated ERK and Drp1 induced by pharmacological ascorbate (P-AscH-) were reversed with genetic and pharmacological inhibitors of ERK and Drp1.•Pharmacological ascorbate increased mitochondrial fission after treatment with pharmacological ascorbate.•Pharmacological ascorbate decreased in vitro and in vivo growth which was enhanced by genetic and pharmacological inhibition of both ERK and Drp1.•Pharmacological ascorbate induces sustained increases in mitochondrial oxidative stress and changes in mitochondrial dynamics, through activation of the ERK/Drp1 signaling pathway.
Details
- Title: Subtitle
- Pharmacological ascorbate induces sustained mitochondrial dysfunction
- Creators
- Rory S. Carroll - University of IowaJuan Du - University of IowaBrianne R. O'Leary - University of IowaGarett Steers - University of IowaPrabhat C. Goswami - University of IowaGarry R. Buettner - University of IowaJoseph J. Cullen - Departments of Surgery, University of Iowa College of Medicine, USA
- Resource Type
- Journal article
- Publication Details
- Free radical biology & medicine, Vol.204, pp.108-117
- DOI
- 10.1016/j.freeradbiomed.2023.04.023
- PMID
- 37137343
- PMCID
- PMC10375417
- NLM abbreviation
- Free Radic Biol Med
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Publisher
- Elsevier Inc
- Grant note
- P01 CA217797; CA148062; CA184051 / NIH
- Language
- English
- Date published
- 05/01/2023
- Academic Unit
- Surgery; Radiation Oncology
- Record Identifier
- 9984400640802771
Metrics
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