Radiation-Induced Myofibroblasts Promote Tumor Growth via Mitochondrial ROS–Activated TGFβ Signaling

Shimura, Tsutomu; Sasatani, Megumi; Kawai, Hidehiko; Kamiya, Kenji; Kobayashi, Junya; Komatsu, Kenshi; Kunugita, Naoki

doi:10.1158/1541-7786.mcr-18-0321

Cited by 38 publications

(33 citation statements)

References 43 publications

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“…ROS can be derived from different sources, including the mitochondria electron transport chain, xanthine oxidase, the cytochrome P450 system, uncoupled nitric oxide synthase, and myeloperoxidase. ROS also mainly comes from two main parts, mitochondrial and NADPH oxidase after radiation ( Bedard and Krause, 2007 ; Bhattacharyya et al., 2014 ; Cho et al., 2017 ; Pei et al., 2017 ; Kawamura et al., 2018 ; Sakai et al., 2018 ; Shimura et al., 2018 ; Mortezaee et al., 2019 ). To explore the origin of ROS induced by 1α,25(OH) 2 D 3 , both NADPH oxidase inhibitors, DPI and Apocynin, and the mitochondrial membrane potential were used to determine the source of ROS ( Bedard and Krause, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway

Nie

et al. 2020

Front. Pharmacol.

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The radioresistance of tumors affect the outcome of radiotherapy. Accumulating data suggest that 1a,25(OH) 2 D 3 is a potential anti-oncogenic molecule in various cancers. In the present study, we investigated the radiosensitive effects and underlying mechanisms of 1a,25(OH) 2 D 3 in vitro and in vivo. We found that 1a,25(OH) 2 D 3 enhanced the radiosensitivity of lung cancer and ovarian cancer cells by promoting the NADPH oxidase-ROS-apoptosis axis. Compared to the group that only received radiation, the survival fraction and selfrenewal capacity of cancer cells treated with a combination of 1a,25(OH) 2 D 3 and radiation were decreased. Both apoptosis and ROS were significantly increased in the combination group compared with the radiation only group. Moreover, N-acetyl-L-cysteine, a scavenger of intracellular ROS, reversed the apoptosis and ROS induced by 1a,25(OH) 2 D 3 , indicating that 1a,25(OH) 2 D 3 enhanced the radiosensitivity of cancer cells in vitro by promoting ROSinduced apoptosis. Moreover, our results demonstrated that 1a,25(OH) 2 D 3 promoted the ROS level via activating NADPH oxidase complexes, NOX4, p22 phox , and p47 phox. In addition, knockdown of the vitamin D receptor (VDR) abolished the radiosensitization of 1a,25(OH) 2 D 3 , which confirmed that 1a,25(OH) 2 D 3 radiosensitized tumor cells that depend on VDR. Similarly, our study also evidenced that vitamin D 3 enhanced the radiosensitivity of cancer cells in vivo and extended the overall survival of mice with tumors. In summary, these results demonstrate that 1a,25(OH) 2 D 3 enhances the radiosensitivity depending on VDR and activates the NADPH oxidase-ROS-apoptosis axis. Our findings suggest that 1a,25 (OH) 2 D 3 in combination with radiation enhances lung and ovarian cell radiosensitivity, potentially providing a novel combination therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway

Nie

et al. 2020

Front. Pharmacol.

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“…Since individual radiation sensitivity may influence dose assessment, biodosimetry may be able to screen a highly radiation sensitive population in large nuclear incidents. We previously reported that excessive mitochondrial ROS activates transforming growth factor-beta (TGF-β) signaling, thereby inducing myofibroblast differentiation and facilitating tumor growth through tumor microenvironment formation (TME) formation [35]. ROS-mediated mitochondrial damage is associated with TME via fibroblast activation [35].…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that excessive mitochondrial ROS activates transforming growth factor-beta (TGF-β) signaling, thereby inducing myofibroblast differentiation and facilitating tumor growth through tumor microenvironment formation (TME) formation [35]. ROS-mediated mitochondrial damage is associated with TME via fibroblast activation [35]. Consequently, use of oxidative biological markers serves both radiation dose assessment and evaluation of radiation risks for humans.…”

Section: Discussionmentioning

confidence: 99%

Induction of oxidative stress biomarkers following whole-body irradiation in mice

et al. 2020

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Dose assessment is an important issue for radiation emergency medicine to determine appropriate clinical treatment. Hematopoietic tissues are extremely vulnerable to radiation exposure. A decrease in blood cell count following radiation exposure is the first quantitative bio-indicator using hematological techniques. We further examined induction of oxidative stress biomarkers in residual lymphocytes to identify new biomarkers for dosimetry. In vivo whole-body radiation to mice exposed to 5 Gy significantly induces DNA double-strand breaks, which were visualized by γ-H2AX in mouse blood cells. Mouse blood smears and peripheral blood mononuclear cells (PBMC) isolated from irradiated mice were used for immunostaining for oxidative biomarkers, parkin or Nrf2. Parkin is the E3 ubiquitin ligase, which is normally localized in the cytoplasm, is relocated to abnormal mitochondria with low membrane potential (ΔΨm), where it promotes clearance via mitophagy. Nrf2 transcription factor controls the major cellular antioxidant responses. Both markers of oxidative stress were more sensitive and persistent over time than nuclear DNA damage. In conclusion, parkin and Nrf2 are potential biomarkers for use in radiation dosimetry. Identification of several biological markers which show different kinetics for radiation response is essential for radiation dosimetry that allows the assessment of radiation injury and efficacy of clinical treatment in emergency radiation incidents. Radiation-induced oxidative damage is useful not only for radiation dose assessment but also for evaluation of radiation risks on humans.

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“…Azithromycin is able to concentrate in intracellular compartments, mainly in fibroblasts, hepatocytes, phagocytic cells, and white blood cells, where concentrations reach up to 321 µM (240 µg/mL), approximately 1000 times that of C max . Shimura et al [21] reported that mitochondrial ROS of myofibroblasts induced by radiation activated TGF β signaling and promoted tumor growth. Numerous studies provide evidence that chronic inflammation increases the risk of cancer [22,23].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Toxicity of Azithromycin Results in Aerobic Glycolysis and DNA Damage of Human Mammary Epithelia and Fibroblasts

Jiang¹,

Baucom²,

Elliott³

2019

Antibiotics

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Mitochondria evolved from free-living bacteria via endocytosis within eukaryotic host cells millions of year ago. We hypothesized that antibiotics cause mammalian mitochondrial damage while causing bacterial lethality. Mitochondrial toxicity of azithromycin in human mammary epithelia MCF-12A and fibroblasts were tested by fluorescent and transmission electron microscopy. Gene expression and DNA damage were tested by real-time polymerase chain reaction (qPCR) and ELISA. We found azithromycin suppressed the mitochondrial membrane potential gradient of MCF-12A cells and fibroblasts. Ultrastructure exams showed that the antibiotic caused vacuolated and swollen mitochondria with disrupted cristae in MCF-12A cells and fibroblasts compared to the morphology of mitochondria in the cells without antibiotic treatment. Fluorescent microscopy also showed azithromycin-induced mitochondrial reactive oxygen species (ROS), superoxide, after 3 h of culture. The DNA oxidative damage product, 8-hydroxy-2’-deoxyguanosine (8-OHdG, significantly increased in the media after MCF-12A cells and fibroblasts were cultured in the media containing azithromycin for 24 h. Azithromycin upregulated gene expression of hypoxia inducible factor 1 alpha (HIF1a), glycolytic enzymes including hexokinase 2 (HK2), phosphofructokinase 1 (PFKM), pyruvate kinase muscle isozyme M2 (PKM2), and glucose transporters in MCF-12A cells and fibroblasts. Lactate production also increased in the culture media. After treatment with azithromycin, healthy MCF-12A and fibroblast cells increased aerobic glycolysis—the “Warburg Effect”—to generate energy. In summary, azithromycin caused mitochondrial toxicity, ROS overproduction, DNA oxidative damage, upregulation of the HIF1a gene, and aerobic glycolysis in healthy mammalian cells. Over-usage of antibiotics could contribute to tumorigenesis and neurodegeneration and aggravate existing mitochondria-associated diseases.

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Radiation-Induced Myofibroblasts Promote Tumor Growth via Mitochondrial ROS–Activated TGFβ Signaling

Cited by 38 publications

References 43 publications

1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway

1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway

Induction of oxidative stress biomarkers following whole-body irradiation in mice

Mitochondrial Toxicity of Azithromycin Results in Aerobic Glycolysis and DNA Damage of Human Mammary Epithelia and Fibroblasts

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