The double-edged roles of ROS in cancer prevention and therapy

Wang, Yawei; Qi, Huan; Liu, Yü; Duan, Chao; Liu, Xiaolong; Xia, Tian; Chen, Di; Piao, Hulin; Liu, Hongxu

doi:10.7150/thno.56747

Cited by 372 publications

(253 citation statements)

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“…In our previous study, we showed the dual roles of ROS in cancer progression: abnormal ROS accumulation induces malignant transformation, while excessive ROS levels that exceed a threshold lead to cell death 5 . We verified this point in LUAD cells and found that H 2 O 2 at a low concentration (≤20 μmol/L) promoted cellular proliferation, but H 2 O 2 at a high concentration (≥40 μmol/L) induced cell death (Figure 4A, C and E).…”

Section: Resultsmentioning

confidence: 99%

AQP3‐mediated H₂O₂ uptake inhibits LUAD autophagy by inactivating PTEN

et al. 2021

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It is widely accepted that redox reprogramming participates in malignant transformation of lung adenocarcinoma (LUAD). However, the source of excessive reactive oxygen species (ROS) and the downstream signaling regulatory mechanism are complicated and unintelligible. In the current study, we newly identified the aquaporin 3 (AQP3) as a LUAD oncogenic factor with capacity to transport exogenous hydrogen peroxide (H2O2) and increase intracellular ROS levels. Subsequently, we demonstrated that AQP3 was necessary for the facilitated diffusion of exogenous H2O2 in LUAD cells and that the AQP3‐dependent transport of H2O2 accelerated cell growth and inhibited rapamycin‐induced autophagy. Mechanistically, AQP3‐mediated H2O2 uptake increased intracellular ROS levels to inactivate PTEN and activate the AKT/mTOR pathway to subsequently inhibit autophagy and promote proliferation in LUAD cells. Finally, we suggested that AQP3 depletion retarded subcutaneous tumorigenesis in vivo and simultaneously decreased ROS levels and promoted autophagy. These findings underscore the importance of AQP3‐induced oxidative stress in malignant transformation and suggest a therapeutic target for LUAD.

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Section: Resultsmentioning

confidence: 99%

AQP3‐mediated H₂O₂ uptake inhibits LUAD autophagy by inactivating PTEN

et al. 2021

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“…H 2 O 2 is highly diffusible and enters the cytoplasm as a second messenger. Moderately increased ROS in hypoxic cancer cells could stabilize HIF-1α and mediate various tumorigenesis-associated signaling pathways, including AKT, NF-κB, AMPK and Notch 55 - 60 . Nevertheless, a vicious cycle between mitochondria damage and ROS generation could threaten the survival of hypoxic cancer cells.…”

Section: Introductionmentioning

confidence: 99%

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia

Li¹,

Wang²,

Li³

et al. 2021

Theranostics

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Background: Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria. Methods: A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O 2 environment. Results: MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells. Conclusions: This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment.

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“…An important aspect of HO-1 expression in cancer cells is the gain of a resistant phenotype. It is well known that conventional anticancer treatments such as chemo- and radio- therapies can act to induce oxidative stress by increasing intracellular ROS levels [ 141 ] in order to favor apoptosis, as recently reviewed by Aggarwal and co-workers [ 142 ]. However, cancer cells, by up-regulating their antioxidant defenses, including HO-1, can counteract oxidative stress.…”

Section: Role Of Ho-1 In Cancer Progressionmentioning

confidence: 99%

Clinical Significance of Heme Oxygenase 1 in Tumor Progression

et al. 2021

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Heme oxygenase 1 (HO-1) plays a key role in cell adaptation to stressors through the antioxidant, antiapoptotic, and anti-inflammatory properties of its metabolic products. For these reasons, in cancer cells, HO-1 can favor aggressiveness and resistance to therapies, leading to poor prognosis/outcome. Genetic polymorphisms of HO-1 promoter have been associated with an increased risk of cancer progression and a high degree of therapy failure. Moreover, evidence from cancer biopsies highlights the possible correlation between HO-1 expression, pathological features, and clinical outcome. Indeed, high levels of HO-1 in tumor specimens often correlate with reduced survival rates. Furthermore, HO-1 modulation has been proposed in order to improve the efficacy of antitumor therapies. However, contrasting evidence on the role of HO-1 in tumor biology has been reported. This review focuses on the role of HO-1 as a promising biomarker of cancer progression; understanding the correlation between HO-1 and clinical data might guide the therapeutic choice and improve the outcome of patients in terms of prognosis and life quality.

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The double-edged roles of ROS in cancer prevention and therapy

Cited by 372 publications

References 248 publications

AQP3‐mediated H₂O₂ uptake inhibits LUAD autophagy by inactivating PTEN

AQP3‐mediated H₂O₂ uptake inhibits LUAD autophagy by inactivating PTEN

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia

Clinical Significance of Heme Oxygenase 1 in Tumor Progression

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The double-edged roles of ROS in cancer prevention and therapy

Cited by 372 publications

References 248 publications

AQP3‐mediated H2O2 uptake inhibits LUAD autophagy by inactivating PTEN

AQP3‐mediated H2O2 uptake inhibits LUAD autophagy by inactivating PTEN

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia

Clinical Significance of Heme Oxygenase 1 in Tumor Progression

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AQP3‐mediated H₂O₂ uptake inhibits LUAD autophagy by inactivating PTEN

AQP3‐mediated H₂O₂ uptake inhibits LUAD autophagy by inactivating PTEN