Abstract
TMET-15. CYTOCHROME C OXIDASE MEDIATES CELLULAR IRON HOMEOSTASIS AND RADIORESISTANCE IN GLIOBLASTOMA
Neuro-oncology (Charlottesville, Va.), Vol.24(Supplement_7), pp.vii264-vii265
11/14/2022
DOI: 10.1093/neuonc/noac209.1020
PMCID: PMC9661282
Abstract
Abstract Defining the molecular mechanism(s) responsible for the adaptive radioresistance in glioblastoma (GBM) is necessary for the development of effective treatment options. The cellular labile iron pool (LIP) is very important for determining the cellular response to radiation, as it contributes to radiation-induced production of reactive oxygen species (ROS). Recently, cytochrome c oxidase (CcO), a mitochondrial heme-containing enzyme also involved in regulating ROS production, was found to be involved in GBM chemoresistance. However, the role of LIP and CcO in GBM radioresistance is not known. Herein, we tested the hypothesis that CcO-mediated alterations in the level of labile iron contribute to adaptive radioresistance. Using an in vitro model of GBM adaptive radioresistance, we found an increase in CcO activity in radioresistant cells that associated with a decrease in the cellular LIP (4.1-fold), decrease in lipid peroxidation (2-fold), and a switch in the CcO subunit 4 (COX4) isoform expression, from COX4-2 to COX4-1. Furthermore, knockdown of COX4-1 in radioresistant GBM cells decreased CcO activity and restored radiosensitivity, whereas overexpression of COX4-1 in radiosensitive cells increased CcO activity and rendered the cells radioresistant. We further observed that radioresistant cells has increased expression of mitoferrin-1, a protein that facilitates the incorporation of iron into mitochondria. Overexpression of mitoferrin-1 in glioma cells increases the activity of mitochondrial protein complexes, decreases the cellular labile iron pool (p< 0.05), and decreases the production of 4-hydroxy nonenal (4-HNE), a lipid peroxidation product. Furthermore, overexpression of mitoferrin-1 significantly increases the anchorage independent colony formation in soft agar assay (p< 0.01). Moreover, mitoferrin-1 overexpressing cells implanted orthotopically in the brain of nude mice significantly decreased survival compared to wild type (p < 0.01). These results indicate that manipulation of cellular and mitochondrial iron homeostasis may provide a strategy to improve therapeutic outcome in patients with GBM.
Details
- Title: Subtitle
- TMET-15. CYTOCHROME C OXIDASE MEDIATES CELLULAR IRON HOMEOSTASIS AND RADIORESISTANCE IN GLIOBLASTOMA
- Creators
- Md Yousuf Ali - University of IowaCasey Pullium - University of IowaSusanne Flor - University of IowaPrabhat Goswami - University of IowaClaudia Oliva - University of IowaCorinne Griguer - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Neuro-oncology (Charlottesville, Va.), Vol.24(Supplement_7), pp.vii264-vii265
- DOI
- 10.1093/neuonc/noac209.1020
- PMCID
- PMC9661282
- ISSN
- 1522-8517
- eISSN
- 1523-5866
- Language
- English
- Date published
- 11/14/2022
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984353496902771
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