Induction of apoptosis by the overexpression of an alternative splicing variant of mitochondrial thioredoxin reductase

Chang, En Young; Son, Seong-Kweon; Ko, Hyun Sook; Baek, Suk‐Hwan; Kim, Jung Hye; Kim, Jae-Ryong

doi:10.1016/j.freeradbiomed.2005.08.008

Cited by 19 publications

(5 citation statements)

References 30 publications

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“…ROS can cause damage to DNA and play a role in triggering carcinogenesis in the liver. CAT, SOD, GPX1, and TXNRD2 are known to reduce ROS (Mates 2000; Chang et al 2005). Among these genes, m- Cat was only the gene induced in the SCID/fenofibrate mouse liver but not in the h-hep regions of Chimera/fenofibrate mice.…”

Section: Discussionmentioning

confidence: 99%

Chimeric Mice with Hepatocyte-humanized Liver as an Appropriate Model to Study Human Peroxisome Proliferator–activated Receptor-α

Tateno

Yamamoto²,

Utoh³

et al. 2014

Toxicol Pathol

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Peroxisome proliferator (PP)-activated receptor-a (PPARa) agonists exhibit species-specific effects on livers of the rodent and human (h), which has been considered to reside in the difference of PPARa gene structures. However, the contribution of h-hepatocytes (heps) to the species-specificity remains to be clarified. In this study, the effects of fenofibrate were investigated using a hepatocyte-humanized chimeric mouse (m) model whose livers were replaced with h-heps at >70%. Fenofibrate induced hepatocellular hypertrophy, cell proliferation, and peroxisome proliferation in livers of severe combined immunodeficiency (SCID) mice, but not in the h-hep of chimeric mouse livers. Fenofibrate increased the expression of the enzymes of b-and !-hydroxylation and deoxygenation of lipids at both gene and protein levels in SCID mouse livers, but not in the h-heps of chimeric mouse livers, supporting the studies with h-PPARa-transgenic mice, a hitherto reliable model for studying the regulation of h-PPARa in the hliver in most respects, except the induction of the peroxisome proliferation. This study indicates the importance of not only h-PPARa gene but also h-heps themselves to correctly predict effects of fibrates on h-livers, and, therefore, suggests that the chimeric mouse is a currently available, consistent, and reliable model to obtain pharmaceutical data concerning the effects of fibrates on h-livers.

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Section: Discussionmentioning

confidence: 99%

Chimeric Mice with Hepatocyte-humanized Liver as an Appropriate Model to Study Human Peroxisome Proliferator–activated Receptor-α

Tateno

Yamamoto²,

Utoh³

et al. 2014

Toxicol Pathol

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“…All Txnrd genes are transcribed in a complex manner, resulting in divergent forms of each isoenzyme that differ from each other mainly in their NH 2 -terminal domains (88,95,139,211,442,455,507,572,573,622,629), potentially reflecting many levels of regulation. The phenotypes of mouse knockout models targeting the Txnrd1 and Txnrd2 genes are summarized in TABLE 8.…”

Section: Trxr Familymentioning

confidence: 99%

Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications

Lei

Zhu

Cheng

et al. 2016

Physiological Reviews

333

230

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate "paradoxical" outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of "antioxidant" nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that "paradoxical" roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways.

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“…Interestingly, TrxR knockdown by stable transfection with a small interfering RNA construct has been shown to nearly abolish the capacity of lung cancer cells to form tumors in a xenograft model (Yoo et al 2006). Similarly, overexpression of the alternative splicing variant of TrxR results in a marked induction of apoptosis in cervical cancer cells (Chang et al 2005). These experiments indicate an essential role of TrxR in cancer cell growth; therefore, the development of drugs that inhibit TrxR activity may represent a key strategy for the treatment and prevention of cancer (Powis and Kirkpatrick 2007;Mahmood et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Auranofin, an inhibitor of thioredoxin reductase, induces apoptosis in hepatocellular carcinoma Hep3B cells by generation of reactive oxygen species

Hwangbo¹,

Jeong²,

Han³

et al. 2017

gpb

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Mammalian thioredoxin reductase (TrxR) plays a vital role in restoring cellular redox balance disrupted by reactive oxygen species (ROS) generation and oxidative damage. Here, we evaluated whether auranofin, a selective inhibitor of TrxR, could serve as a potential anti-cancer agent through its selective targeting of TrxR activity in Hep3B hepatocellular carcinoma cells. Auranofin treatment reduced the TrxR activity of these cells and induced apoptosis, which were accompanied by up-regulation of death receptors (DRs) and activation of caspases, as well as promotion of proteolytic degradation of poly(ADP-ribose)-polymerase. Treatment with a pan-caspase inhibitor reversed the auranofin-induced apoptosis and growth suppression, indicating that auranofin may induce apoptosis through a caspase-dependent mechanism involving both the intrinsic and extrinsic apoptotic pathways. Auranofin also significantly altered mitochondrial function, promoting mitochondrial membrane permeabilization and cytochrome c release by regulating Bcl-2 family proteins; these events were accompanied by an accumulation of ROS. Inhibition of ROS generation with the ROS quencher significantly attenuated the inactivation of TrxR in auranofin-treated cells and almost completely suppressed the auranofin-induced up-regulation of DRs and activation of caspases, thereby preventing auranofin-induced apoptosis and loss of cell viability. Taken together, these findings indicate that auranofin inhibition of TrxR activity in Hep3B cells activates ROS- and caspase-dependent apoptotic signaling pathways and triggers cancer cell death.

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Induction of apoptosis by the overexpression of an alternative splicing variant of mitochondrial thioredoxin reductase

Cited by 19 publications

References 30 publications

Chimeric Mice with Hepatocyte-humanized Liver as an Appropriate Model to Study Human Peroxisome Proliferator–activated Receptor-α

Chimeric Mice with Hepatocyte-humanized Liver as an Appropriate Model to Study Human Peroxisome Proliferator–activated Receptor-α

Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications

Auranofin, an inhibitor of thioredoxin reductase, induces apoptosis in hepatocellular carcinoma Hep3B cells by generation of reactive oxygen species

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