Lipid peroxidation increases hydrogen peroxide permeability leading to cell death in cancer cell lines that lack mtDNA

4‐Hydroxynonenal (HNE) is an important product of plasma membrane lipid peroxidation, which is a cause of cell and tissue injury. Mitochondrial DNA (mtDNA)‐depleted ρ0 cells were established using human cervical cancer and oral squamous cell carcinoma cell lines. We investigated the effect of reacti...

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Bibliographic Details
Published in:Cancer science 2019-09, Vol.110 (9), p.2856-2866
Main Authors: Tomita, Kazuo, Takashi, Yuko, Ouchi, Yuya, Kuwahara, Yoshikazu, Igarashi, Kento, Nagasawa, Taisuke, Nabika, Hideki, Kurimasa, Akihiro, Fukumoto, Manabu, Nishitani, Yoshihiro, Sato, Tomoaki
Format: Article
Language:English
Subjects:
Aldehydes - metabolism
Antitumor agents
Apoptosis
Apoptosis - drug effects
Arachidonate 15-Lipoxygenase - metabolism
Cell death
Cell Line, Tumor
cell membrane
Cell Membrane - metabolism
Cell Membrane Permeability - genetics
Cervical cancer
Cervix
Cyclooxygenase-2
Cytoplasm
DNA, Mitochondrial - genetics
Drug Resistance, Neoplasm
Electron Transport Chain Complex Proteins - genetics
Electron Transport Chain Complex Proteins - metabolism
Humans
Hydrogen peroxide
Hydrogen Peroxide - administration & dosage
Hydrogen Peroxide - metabolism
Hydrogen Peroxide - pharmacokinetics
Kinases
Lipid peroxidation
Lipid Peroxidation - genetics
Lipoxygenase
mitochondria
Mitochondria - genetics
Mitochondria - metabolism
Mitochondrial DNA
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - pathology
Oral squamous cell carcinoma
Original
Oxidation
Oxidative stress
Oxidative Stress - drug effects
Permeability
Phospholipid Ethers - administration & dosage
Reactive oxygen species
Squamous cell carcinoma
Tumor cell lines
Up-Regulation
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Summary:4‐Hydroxynonenal (HNE) is an important product of plasma membrane lipid peroxidation, which is a cause of cell and tissue injury. Mitochondrial DNA (mtDNA)‐depleted ρ0 cells were established using human cervical cancer and oral squamous cell carcinoma cell lines. We investigated the effect of reactive oxygen species in ρ0 cells, especially the mechanism of hydrogen peroxide (H2O2)‐mediated cell death. These cell were subjected to high oxidative stress and, compared with their parental cells, showed greater sensitivity to H2O2 and high lipid peroxidation. Upregulation of HNE in the plasma membrane was observed prior to the increase in intracellular H2O2. The amount of oxidized lipid present changed H2O2 permeability and administration of oxidized lipid led to further cell death after treatment with H2O2. Expression levels of lipoxygenase ALOX genes (ie ALOX5, ALOX12, and ALOX15) were upregulated in ρ0 cells, as were expression levels of ALOX12 and ALOX15 proteins. ALOX5 protein was mainly distributed in the nucleus, while ALOX12 and ALOX15 proteins were distributed in the nucleus and the cytoplasm. Although expression of COX2 gene was upregulated, its protein expression did not increase. ALOX (especially ALOX15) may be involved in the sensitivity of cancer cells to treatment. These data offer promise for the development of novel anticancer agents by altering the oxidation state of the plasma membrane. Our results showed that lipid peroxidation status is important for H2O2 sensitivity and that ALOX15 is involved in lipid peroxidation status. Using mitochondrial DNA depleted ρ0 cells, we found high lipid peroxidation in these cells. Our results show that the lipid peroxidation status is important to H2O2 sensitivity and involvement of lipoxygenase 15 in this lipid peroxidation status.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.14132