Dissertation
Regulation of iron metabolism in radioresistant glioblastoma
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2022
DOI: 10.25820/etd.006769
Abstract
Glioblastoma (GBM) is the most common and most lethal adult primary malignant brain tumor. Median progression-free and overall survival after initial diagnosis are 6.2-7.5 and 14-20 months, respectively, even with a highly aggressive standard-of-care treatment. One of the main reasons for this poor survival is development of resistance to standard of care therapy, especially, resistance to radiotherapy. Defining the molecular mechanism(s) responsible for the adaptive radioresistance in 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 LIP contribute to adaptive radioresistance. Using an in vitro model of GBM adaptive radioresistance, we found an increase in CcO activity in radioresistant cells that is associated with a decrease in the cellular LIP, a decrease in lipid peroxidation and a switch in the CcO subunit 4 (COX4) isoform expression, from COX4-2 to COX4-1. We further observed that radioresistant cells have increased expression of mitoferrin-1 (MFRN1), a protein that facilitates the incorporation of iron into mitochondria. Overexpression of MFRN1 in glioma cells increases the activity of mitochondrial protein complexes, a decrease in cellular LIP, and a decrease in production of 4-hydroxy nonenal (4-HNE), a lipid peroxidation product. Furthermore, MFRN1 overexpression also enhances the proliferation rate and anchorage independent growth. Moreover, MFRN1 overexpression significantly decreased survival in an orthotopic mouse model of glioma. These results indicate that manipulation of cellular and mitochondrial iron homeostasis may provide a novel strategy to improve therapeutic outcome in patients with GBM.
Details
- Title: Subtitle
- Regulation of iron metabolism in radioresistant glioblastoma
- Creators
- Md Yousuf Ali
- Contributors
- Corinne E Griguer (Advisor)Douglas R Spitz (Committee Member)Prabhat C Goswami (Committee Member)Gabriele Ludewig (Committee Member)Larry W Robertson (Committee Member)Bryan G Allen (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Human Toxicology
- Date degree season
- Autumn 2022
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006769
- Number of pages
- x, 93 pages
- Copyright
- Copyright 2022 Md Yousuf Ali
- Language
- English
- Description illustrations
- Illustrations, charts, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 71-93).
- Public Abstract (ETD)
Glioblastoma (GBM) is a type of malignant brain tumor. Patients with this disease have a very low survival rate after diagnosis. One of the main treatment options for these patients is radiotherapy. One of the reasons for GBM poor outcomes is the development of radioresistance. Therefore, it is important to understand why GBM patients develop resistance against radiation. We developed radioresistant GBM cells by exposing radiosensitive cells to fractionated radiation up to 45 Gy. We then investigated those models to understand why tumors become resistant to radiation. We have found that cytochrome c oxidase (CcO), also known as complex IV in the mitochondrial electron transport chain (ETC), and cellular iron metabolism play crucial roles in the development of radioresistance. Moreover, we have also found that MFRN1, a protein which transports iron from the cytoplasm to the mitochondria, is also an essential component in this mechanism. Our findings indicate that targeting iron metabolism could be an effective therapeutic strategy to sensitize radioresistant GBM tumors to radiation.
- Academic Unit
- Interdisciplinary Graduate Program in Human Toxicology
- Record Identifier
- 9984362857702771
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