Auranofin Promotes Mitochondrial Apoptosis by Inducing Annexin A5 Expression and Translocation in Human Prostate Cancer Cells

Park, Nahee; Chun, Young‐Jin

doi:10.1080/15287394.2014.955834

Cited by 33 publications

(24 citation statements)

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ After glucose depletion, pIRES cell death was caused by mild necrosis and by early intrinsic apoptosis as documented by the increased percentages of PI -CaspACE + and PI -Annexin V + cells. In this context, phosphatidylserine externalization from the inner to the outer membrane site as requirement for the binding of Annexin V dye has been identified as an early and prominent feature of mitochondrially-mediated apoptosis 14,15 . Therefore, we estimated the increased percentages of PI -CaspACE + and PI -Annexin V + cells following glucose depletion as indicator of an intrinsic, mitochondrially-mediated apoptosis path where phosphatidylserine externalization is accompanied by the activation of caspases.…”

Section: Discussionmentioning

confidence: 99%

Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation

Wanka

Lutze

Staar

et al. 2020

Sci Rep

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Although the renin-angiotensin system usually promotes oxidative stress and cell death, renin transcripts have been discovered, whose transcription product may be cardioprotective. these transcripts encode a non-secretory renin isoform that is localized in the cytosol and within mitochondria. Here we tested the hypotheses that cytosolic renin [ren(2-9)] expression promotes cell survival under hypoxia and glucose depletion by preserving the mitochondrial membrane potential (∆Ψ m ) and mitigating the accumulation of ROS. To simulate ischemic insults, we exposed H9c2 cells to glucose deprivation, anoxia or to combined oxygen-glucose deprivation (OGD) for 24 hours and determined renin expression. Furthermore, H9c2 cells transfected with the empty pIRES vector (pIRES cells) or ren(2-9) cDNA-containing vector [ren(2-9) cells] were analyzed for cell death, ∆Ψ m , Atp levels, accumulation of RoS, and cytosolic ca 2+ content. In pIRES cells, expression of ren(1A-9) was stimulated under all three ischemia-related conditions. After oGD, the cells lost their ∆Ψ m and exhibited enhanced RoS accumulation, increased cytosolic ca 2+ levels, decreased Atp levels as well as increased cell death. In contrast, ren(2-9) cells were markedly protected from these effects. Ren(2-9) appears to represent a protective response to oGD by reducing RoS generation and preserving mitochondrial functions. therefore, it is a promising new target for the prevention of ischemia-induced myocardial damage.Myocardial infarction is a major cause of death worldwide. Given the high incidence of myocardial infarction and the associated cardiac injury, developing novel strategies and countermeasures to protect the heart against acute and especially ischemia/reperfusion-induced damage is of great interest.Renin is known as secretory glycoprotein that generates angiotensin (ANG) I from angiotensinogen. ANG I is further cleaved to ANG II by the angiotensin-converting enzyme. ANG II increases blood pressure as well as salt-and water reabsorption. Furthermore, ANG II enhances oxidative stress, exerts pro-inflammatory effects and induces apoptotic and necrotic cell death, particularly in the heart and the kidney. Correspondingly, inhibitors of the renin-angiotensin system (RAS) are among the most potent drugs in the treatment of hypertension and cardiac failure, markedly increasing the life span of patients 1 .Alternative renin transcripts, termed exon1A renin, exon(2-9)renin, renin-b or renin-c, have been identified in rats and mice 2,3 as well as in transgenic mice expressing a human renin gene construct 4 . In the rat heart, exon(1A-9) renin transcription is under the control of an alternative promoter located in intron 1 5 . In cardiac cells, this promoter is stimulated by glucose depletion in a serum response factor-dependent manner 5 . Furthermore, exon(1A-9) renin mRNA abundance increased markedly after myocardial infarction in vivo 6 . Due to the absence of the signal for a co-translational transport to the endoplasmatic reticulum, encoded by exon1, all a...

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Section: Discussionmentioning

confidence: 99%

Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation

Wanka

Lutze

Staar

et al. 2020

Sci Rep

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“…Auranofin as an inhibitor of TrxR has an anti-inflammatory effect (17) and can treat rheumatoid arthritis (18). In addition, auranofin shows anticancer effects in ovarian, prostate, breast and lung cancer cells (14,(19)(20)(21). It is also reported that many cancer cells contain high level of TrxR expression (6,22).…”

Section: Discussionmentioning

confidence: 99%

Auranofin induces mesothelioma cell death through oxidative stress and GSH depletion

You

Park

2015

Oncology Reports

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Mesothelioma is an aggressive tumor associated with asbestos exposure. Auranofin as an inhibitor of thioredoxin reductase (TrxR) affects many biological processes such as inflammation and proliferation. In the present study, we investigated the cellular effects of auranofin on patient-derived mesothelioma cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Basal TrxR1 levels have no difference between mesothelial cells and certain mesothelioma cells. In particular, ADA, CON and Hmeso mesothelioma cells showed lower levels of TrxR1 expression. Auranofin inhibited the proliferation of mesothelioma cells in a dose-dependent manner. Among mesothelioma cells were ADA and CON cells sensitive to auranofin. This agent also induced caspase-independent apoptosis and necrosis in ADA cells. In addition, auranofin increased ROS levels including O2(•-) and induced GSH depletion in mesothelioma cells. While N-acetyl cysteine (NAC) prevented cell death and decreased ROS levels in auranofin-treated mesothelioma cells, L-buthionine sulfoximine (BSO) intensified apoptosis and GSH depletion in these cells. In conclusion, auranofin induced mesothelioma cell death through oxidative stress and the death was regulated by the status of GSH content.

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“…Of them, PAI-2 was increased in annexin A5 knockdown cells and was decreased in annexin A5-overexpressing cells. Previous study revealed that auranofin increases annexin A5 expression and translocation into mitochondria to induce apoptosis through oligomerization of VDAC in PC-3 cells (Park and Chun, 2014). Hence, we treated auranofin to induce annexin A5-mediated apoptosis and observed the PAI-2 level resulting in reduction of PAI-2 expression in a concentration-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Phase I/II clinical trials of auranofin to treat chronic lymphocytic leukemia has been completed (Liu et al ., 2014; Clinicaltrials.gov, 2016). Moreover, our recent study suggested that auranofin leads to annexin A5 expression and translocation into mitochondria causing mitochondrial apoptosis through VDAC oligomerization in human prostate cancer cells (Park and Chun, 2014). …”

Section: Introductionmentioning

confidence: 99%

Auranofin Suppresses Plasminogen Activator Inhibitor-2 Expression through Annexin A5 Induction in Human Prostate Cancer Cells

Shin

Kwon

et al. 2016

Biomol Ther (Seoul)

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Auranofin has been developed as antirheumatic drugs, which is currently under clinical development for the treatment of chronic lymphocytic leukemia. Previous report showed that auranofin induced apoptosis by enhancement of annexin A5 expression in PC-3 cells. To understand the role of annexin A5 in auranofin-mediated apoptosis, we performed microarray data analysis to study annexin A5-controlled gene expression in annexin A5 knockdown PC-3 cells. Of differentially expressed genes, plasminogen activator inhibitor (PAI)-2 was increased by annexin A5 siRNA confirmed by qRT-PCR and western blot. Treatment with auranofin decreased PAI-2 and increased annexin A5 expression as well as promoting apoptosis. Furthermore, auranofin-induced apoptosis was recovered by annexin A5 siRNA but it was promoted by PAI-2 siRNA. Interestingly, knockdown of annexin A5 rescued PAI-2 expression suppressed by auranofin. Taken together, our study suggests that induction of annexin A5 by auranofin may enhance apoptosis through suppression of PAI-2 expression in PC-3 cells.

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Auranofin Promotes Mitochondrial Apoptosis by Inducing Annexin A5 Expression and Translocation in Human Prostate Cancer Cells

Cited by 33 publications

References 24 publications

Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation

Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation

Auranofin induces mesothelioma cell death through oxidative stress and GSH depletion

Auranofin Suppresses Plasminogen Activator Inhibitor-2 Expression through Annexin A5 Induction in Human Prostate Cancer Cells

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