Thioredoxin-dependent regulation of AIF-mediated DNA damage

Shelar, Sandeep; Kaminska, Kamila K.; Reddy, Shridhivya A.; Kumar, Dilip; Tan, Chong Teik; Yu, Victor C.; Lu, Jun; Holmgren, Arne; Hagen, Thilo; Chew, Eng‐Hui

doi:10.1016/j.freeradbiomed.2015.06.029

Cited by 43 publications

(26 citation statements)

References 58 publications

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“…It is well known that Bax interacts with Bcl-2, promotes cytochrome c release, and activates the endogenous apoptosis pathway, which is abolished by survivin [24]. AIF transfers from the mitochondria to the cytoplasm, and then enters the nucleus, causing nuclear DNA aggregate and fractures [25]. ING5 overexpression up-regulated the expression of pro-apoptotic proteins AIF and cytochrome c, and down-regulated the expression of anti-apoptotic proteins Bcl-2, XIAP and survivin, accounting for its apoptosis-induced role in lung cancer cells by mitochondrial pathway.…”

Section: Discussionmentioning

confidence: 99%

The down-regulated ING5 expression in lung cancer: A potential target of gene therapy

et al. 2016

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ING5 can interact with p53, thereby inhibiting cell growth and inducing apoptosis. We found that ING5 overexpression not only inhibited proliferation, migration, and invasion, but also induced G2 arrest, differentiation, autophagy, apoptosis, glycolysis and mitochondrial respiration in lung cancer cells. ING5 transfection up-regulated the expression of Cdc2, ATG13, ATG14, Beclin-1, LC-3B, AIF, cytochrome c, Akt1/2/3, ADFP, PFK-1 and PDPc, while down-regulated the expression of Bcl-2, XIAP, survivin,β-catenin and HXK1. ING5 transfection desensitized cells to the chemotherapy of MG132, paclitaxel, and SAHA, which paralleled with apoptotic alteration. ING5 overexpression suppressed the xenograft tumor growth by inhibiting proliferation and inducing apoptosis. ING5 expression level was significantly higher in normal tissue than that in lung cancer at both protein and mRNA levels. Nuclear ING5 expression was positively correlated with ki-67 expression and cytoplasmic ING5 expression. Cytoplasmic ING5 expression was positively associated with lymph node metastasis, and negatively with age, lymphatic invasion or CPP32 expression. ING5 expression was different in histological classification: squamous cell carcinoma > adenocarcinoma > large cell carcinoma > small cell carcinoma. Taken together, our data suggested that ING5 downregulation might involved in carcinogenesis, growth, and invasion of lung cancer and could be considered as a promising marker to gauge the aggressiveness of lung cancer. It might be employed as a potential target for gene therapy of lung cancer.

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Section: Discussionmentioning

confidence: 99%

The down-regulated ING5 expression in lung cancer: A potential target of gene therapy

et al. 2016

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“…Third, evading apoptosis is one of the hallmarks of malignant cells . The reduced Trx, but not the oxidized Trx, directly binds to several apoptosis‐regulating proteins to inhibit apoptosis, and inhibition of TrxR may promote apoptosis, which also contributes positively to cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

135

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Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.

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“…AIF translocates to the nucleus and binds to the nuclear DNA, triggering condensation and fragmentation [107][108][109] . Importantly this nuclear translocation of AIF has also been observed in cells exposed to sublethal doses of oxidative stress [110] , suggesting that release of mitochondrial proteins like AIF can result in DNA damage without triggering apoptosis.…”

Section: Other Links Between the Mitochondria And Nuclear Functionmentioning

confidence: 88%

Genomic heterogeneity meets cellular energetics: crosstalk between the mitochondria and the cell cycle

Herrera¹,

Azzam²,

Berger³

et al. 2018

JCMT

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Changes in cellular energetics and genomic instability are two characteristics of cancers that have been studied independently. Evidence of cross-talk between mitochondria function and nuclear function has started to emerge, suggesting that these pathways can influence one another. Here we review recent evidence that links the mitochondria and the cell cycle. This evidence indicates bidirectional cross-talk where mitochondria function can regulate the cell cycle and induce genomic instability, and conversely, the cell cycle machinery regulates mitochondria function. Implications for this cross-talk in the development of cancer are discussed.

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Thioredoxin-dependent regulation of AIF-mediated DNA damage

Cited by 43 publications

References 58 publications

The down-regulated ING5 expression in lung cancer: A potential target of gene therapy

The down-regulated ING5 expression in lung cancer: A potential target of gene therapy

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Genomic heterogeneity meets cellular energetics: crosstalk between the mitochondria and the cell cycle

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