Involvement of Caveolin-1 in Repair of DNA Damage through Both Homologous Recombination and Non-Homologous End Joining

Zhu, Hua; Yue, Jingyin; Pan, Zui; Wu, Hao; Cheng, Yan; Lu, Huimei; Ren, Xingcong; Yao, Ming; Shen, Zhiyuan; Yang, Jin Ming

doi:10.1371/journal.pone.0012055

Cited by 35 publications

(34 citation statements)

References 53 publications

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“…Our results showed that in two BLBC cell lines, when cells were pretreated with CAV-1 siRNA, DNA-PKcs phosphorylation at T2609 and the increase in KU70/80 following irradiation were specifically abolished, accompanied by increased and sustained DNA damage. Moreover, Zhu et al observed decreased levels of phospho-ATM (Ser 1981) and phospho-checkpoint kinase 2 (CHK2) (Thr 68) and fewer BRCA1 foci upon caveolin-1 knockdown [46]. Taken together, both our data and that of others have demonstrated that caveolin-1 knockdown mitigates the ability of cells to repair DNA damage.…”

Section: Discussionsupporting

confidence: 81%

Knockdown of CAVEOLIN-1 Sensitizes Human Basal-Like Triple-Negative Breast Cancer Cells to Radiation

Zou

Xia

et al. 2017

Cell Physiol Biochem

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Background/Aims: Triple-negative breast cancer (TNBC) is a high-risk breast cancer phenotype without specific targeted therapy options and is significantly associated with increased local recurrence in patients treated with radiotherapy. CAVEOLIN-1 (CAV-1)-mediated epidermal growth factor receptor (EGFR) nuclear translocation following irradiation promotes DNA repair and thus induces radiation resistance. In this study, we aimed to determine whether knockdown of CAV-1 enhances the radiosensitivity of basal-like TNBC cell lines and to explore the possible mechanisms. Methods: Western blotting was used to compare protein expression in a panel of breast cancer cell lines. Nuclear accumulation of EGFR as well as DNA repair and damage at multiple time points following irradiation with or without CAV-1 siRNA pretreatment were investigated using western blotting and confocal microscopy. The radiosensitizing effect of CAV-1 siRNA was evaluated using a clonogenic assay. Flowcytometry was performed to analyse cell apoptosis and cell cycle alteration. Results: We found that CAV-1 is over-expressed in basal-like TNBC cell lines and barely expressed in HER-2-positive cells; additionally, we observed that HER-2-positive cell lines are more sensitive to irradiation than basal-like TNBC cells. Our findings revealed that radiation-induced EGFR nuclear translocation was impaired by knockdown of CAV-1. In parallel, radiation-induced elevation of DNA repair proteins was also hampered by pretreatment with CAV-1 siRNA before irradiation. Silencing of CAV-1 also promoted DNA damage 24 h after irradiation. Colony formation assays verified that cells could be radiosensitized after knockdown of CAV-1. Furthermore, G₂/M cell cycle arrest and apoptosis enhancement may also contribute to the radiosensitizing effect of CAV-1 siRNA. Conclusion: Our results support the hypothesis that CAV-1 knockdown by siRNA causes increased radiosensitivity in basal-like TNBC cells. The mechanisms associated with this effect are reduced DNA repair through delayed CAV-1-associated EGFR nuclear accumulation and induction of G₂/M arrest and apoptosis through the combined effects of CAV-1 siRNA and radiation.

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Section: Discussionsupporting

confidence: 81%

Knockdown of CAVEOLIN-1 Sensitizes Human Basal-Like Triple-Negative Breast Cancer Cells to Radiation

Zou

Xia

et al. 2017

Cell Physiol Biochem

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“…Recent reports have identified novel roles of BRCA1 in the regulation of caveolin-1 ( CAV-1 ) transcription and the inhibition of cell invasiveness (219), as well as the physical association with plasma membrane proteins ezrin-radixin-moesin, thus controlling cell spreading and motility, which have significant implications for tumor invasion and metastasis (220). Interestingly, the CAV-1 gene is upregulated in cells treated with ionizing radiation and its expression protects cells after exposure through modulating activities of both the HR and NHEJ pathways (221). …”

Section: Role Of Cell Cycle Checkpoint Control and Dna Repair Genes Imentioning

confidence: 99%

DNA Damage Response Genes and the Development of Cancer Metastasis

Broustas¹,

Lieberman²

2014

Radiation Research

235

159

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DNA damage response genes play vital roles in the maintenance of a healthy genome. Defects in cell cycle checkpoint and DNA repair genes, especially mutation or aberrant downregulation, are associated with a wide spectrum of human disease, including a predisposition to the development of neurodegenerative conditions and cancer. On the other hand, upregulation of DNA damage response and repair genes can also cause cancer, as well as increase resistance of cancer cells to DNA damaging therapy. In recent years, it has become evident that many of the genes involved in DNA damage repair have additional roles in tumorigenesis, most prominently by acting as transcriptional (co-) factors. Although defects in these genes are causally connected to tumor initiation, their role in tumor progression is more controversial and it seems to depend on tumor type. In some tumors like melanoma, cell cycle checkpoint/DNA repair gene upregulation is associated with tumor metastasis, whereas in a number of other cancers the opposite has been observed. Several genes that participate in the DNA damage response, such as RAD9, PARP1, BRCA1, ATM and TP53 have been associated with metastasis by a number of in vitro biochemical and cellular assays, by examining human tumor specimens by immunohistochemistry or by DNA genomewide gene expression profiling. Many of these genes act as transcriptional effectors to regulate other genes implicated in the pathogenesis of cancer. Furthermore, they are aberrantly expressed in numerous human tumors and are causally related to tumorigenesis. However, whether the DNA damage repair function of these genes is required to promote metastasis or another activity is responsible (e.g., transcription control) has not been determined. Importantly, despite some compelling in vitro evidence, investigations are still needed to demonstrate the role of cell cycle checkpoint and DNA repair genes in regulating metastatic phenotypes in vivo.

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“…Cav-1 plays a crucial role in the regulation of various physiological and pathophysiological processes such as oncogenic transformation, tumorigenesis, tumor invasion and metastasis (42). Furthermore, it is a key protein involved in anoikis tumor metastasis (43), as well as a promising biomarker for identifying clinically significant cancer (37).…”

Section: Discussionmentioning

confidence: 99%

Elevated enolase and caveolin-1 in the heart of rats following dexamethasone-induced toxicity

Huang

Liu

2012

Mol Med Report

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Abstract. Dexamethasone (DEX)-induced heart damage is associated with enzyme and protein alterations. The purpose of this study was to investigate DEX-induced alterations in cardiac enolase and caveolin-1 (cav-1) following DEX administration. Male Wistar rats were randomly divided into two groups: a control and a DEX. The DEX group intraperitoneally received DEX at the single dose of 10 mg/kg for 7 consecutive days, and the control was given the same amount of saline via the same route. On day 8, the rats were anesthetized, and a thoracotomy was performed in all animals. Immunohistochemical analysis was performed to evaluate protein expression of enolase and cav-1. Sections were analyzed by digital image analysis. Our results demonstrated that cardiac protein expression of enolase and cav-1 was altered following DEX-induced toxicity in the rat. The expression of enolase and cav-1 was significantly increased after DEX treatment, supported by integrated optical density compared with the control (P<0.05). In conclusion, following DEX-induced toxicity, protein expression of enolase and cav-1 was significantly elevated. The current findings indicate that such alterations would be reflected in abnormal cardiac function, and the proteins identified in this study may be useful in revealing the mechanisms underlying DEX-induced toxicity and also in providing various clues for further research.

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Involvement of Caveolin-1 in Repair of DNA Damage through Both Homologous Recombination and Non-Homologous End Joining

Cited by 35 publications

References 53 publications

Knockdown of CAVEOLIN-1 Sensitizes Human Basal-Like Triple-Negative Breast Cancer Cells to Radiation

Knockdown of CAVEOLIN-1 Sensitizes Human Basal-Like Triple-Negative Breast Cancer Cells to Radiation

DNA Damage Response Genes and the Development of Cancer Metastasis

Elevated enolase and caveolin-1 in the heart of rats following dexamethasone-induced toxicity

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