PMID- 35476930
OWN - NLM
STAT- MEDLINE
DCOM- 20220530
LR  - 20220906
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 185
DP  - 2022 May 20
TI  - Cytochrome c oxidase mediates labile iron level and radioresistance in 
      glioblastoma.
PG  - 25-35
LID - S0891-5849(22)00158-7 [pii]
LID - 10.1016/j.freeradbiomed.2022.04.012 [doi]
AB  - Radiotherapy is an important treatment modality for glioblastoma (GBM), yet the 
      initial effectiveness of radiotherapy is eventually lost due to the development 
      of adaptive radioresistance during fractionated radiation therapy. 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) such as lipid radicals through Fenton reactions. 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, decrease in lipid 
      peroxidation, and a switch in the CcO subunit 4 (COX4) isoform expressed, 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. Overexpression of COX4-1 in radiosensitive cells also 
      significantly reduced the cellular LIP and lipid peroxidation. Pharmacological 
      manipulation of the cellular labile iron level using iron chelators altered CcO 
      activity and the radiation response. Overall, these results demonstrate a 
      mechanistic link between CcO activity and LIP in GBM radioresistance and identify 
      the CcO subunit isoform switch from COX4-2 to COX4-1 as a novel biochemical node 
      for adaptive radioresistance of GBM. Manipulation of CcO and the LIP may restore 
      the sensitivity to radiation in radioresistant GBM cells and thereby provide a 
      strategy to improve therapeutic outcome in patients with GBM.
CI  - Copyright (c) 2022. Published by Elsevier Inc.
FAU - Ali, Md Yousuf
AU  - Ali MY
AD  - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The 
      University of Iowa, Iowa City, IA, 52242, USA; Interdisciplinary Graduate Program 
      in Human Toxicology, The University of Iowa, Iowa City, IA, 52242, USA.
FAU - Oliva, Claudia R
AU  - Oliva CR
AD  - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The 
      University of Iowa, Iowa City, IA, 52242, USA.
FAU - Flor, Susanne
AU  - Flor S
AD  - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The 
      University of Iowa, Iowa City, IA, 52242, USA.
FAU - Goswami, Prabhat C
AU  - Goswami PC
AD  - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The 
      University of Iowa, Iowa City, IA, 52242, USA.
FAU - Griguer, Corinne E
AU  - Griguer CE
AD  - Free Radical & Radiation Biology Program, Department of Radiation Oncology, The 
      University of Iowa, Iowa City, IA, 52242, USA. Electronic address: 
      corinne-griguer@uiowa.edu.
LA  - eng
GR  - R01 CA160821/CA/NCI NIH HHS/United States
GR  - R21 NS100054/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220425
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Reactive Oxygen Species)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
SB  - IM
MH  - *Brain Neoplasms/genetics/radiotherapy
MH  - Cell Line, Tumor
MH  - Electron Transport Complex IV/genetics/metabolism
MH  - *Glioblastoma/genetics/radiotherapy
MH  - Humans
MH  - Iron
MH  - Radiation Tolerance/genetics
MH  - Reactive Oxygen Species
OTO - NOTNLM
OT  - COX4-1
OT  - Cytochrome c oxidase
OT  - Glioblastoma
OT  - Iron
OT  - Mitochondria
OT  - Radioresistance
EDAT- 2022/04/28 06:00
MHDA- 2022/05/31 06:00
CRDT- 2022/04/27 20:02
PHST- 2022/02/06 00:00 [received]
PHST- 2022/04/11 00:00 [revised]
PHST- 2022/04/20 00:00 [accepted]
PHST- 2022/04/28 06:00 [pubmed]
PHST- 2022/05/31 06:00 [medline]
PHST- 2022/04/27 20:02 [entrez]
AID - S0891-5849(22)00158-7 [pii]
AID - 10.1016/j.freeradbiomed.2022.04.012 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2022 May 20;185:25-35. doi: 
      10.1016/j.freeradbiomed.2022.04.012. Epub 2022 Apr 25.