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Cross Talk between Two Antioxidant Systems, Thioredoxin and DJ-1: Consequences for Cancer.

Raninga PV, Trapani GD, Tonissen KF - Oncoscience (2014)

Bottom Line: In response to increased ROS levels, cellular antioxidant molecules such as thioredoxin, peroxiredoxins, glutaredoxins, DJ-1, and superoxide dismutases are upregulated to counteract the detrimental effect of ROS.However, targeting one of these antioxidants alone may not be an effective anti-cancer therapy.This review focuses on the cross-talk between thioredoxin and DJ-1 and highlights the importance and consequences of targeting thioredoxin and DJ-1 together to develop an effective anti-cancer therapeutic strategy.

View Article: PubMed Central - PubMed

Affiliation: School of Biomolecular and Physical Sciences, Griffith University, Nathan, Qld, Australia ; Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld, Australia.

ABSTRACT
Oxidative stress, which is associated with an increased concentration of reactive oxygen species (ROS), is involved in the pathogenesis of numerous diseases including cancer. In response to increased ROS levels, cellular antioxidant molecules such as thioredoxin, peroxiredoxins, glutaredoxins, DJ-1, and superoxide dismutases are upregulated to counteract the detrimental effect of ROS. However, cancer cells take advantage of upregulated antioxidant molecules for protection against ROS-induced cell damage. This review focuses on two antioxidant systems, Thioredoxin and DJ-1, which are upregulated in many human cancer types, correlating with tumour proliferation, survival, and chemo-resistance. Thus, both of these antioxidant molecules serve as potential molecular targets to treat cancer. However, targeting one of these antioxidants alone may not be an effective anti-cancer therapy. Both of these antioxidant molecules are interlinked and act on similar downstream targets such as NF-κβ, PTEN, and Nrf2 to exert cytoprotection. Inhibiting either thioredoxin or DJ-1 alone may allow the other antioxidant to activate downstream signalling cascades leading to tumour cell survival and proliferation. Targeting both thioredoxin and DJ-1 in conjunction may completely shut down the antioxidant defence system regulated by these molecules. This review focuses on the cross-talk between thioredoxin and DJ-1 and highlights the importance and consequences of targeting thioredoxin and DJ-1 together to develop an effective anti-cancer therapeutic strategy.

No MeSH data available.


Related in: MedlinePlus

Induction of Trx1 expression by DJ-1 via the Nrf2 pathwayUnder oxidative stress, DJ-1 inhibits the interaction between Nrf2 and its inhibitor Keap1 resulting in activation of Nrf2. Activated Nrf2 translocates to the nucleus and binds the ARE element in the Trx1 promoter and induces Trx1 expression. Figure adapted and used with permission from the authors [135].
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Figure 4: Induction of Trx1 expression by DJ-1 via the Nrf2 pathwayUnder oxidative stress, DJ-1 inhibits the interaction between Nrf2 and its inhibitor Keap1 resulting in activation of Nrf2. Activated Nrf2 translocates to the nucleus and binds the ARE element in the Trx1 promoter and induces Trx1 expression. Figure adapted and used with permission from the authors [135].

Mentions: Trx is usually present in the cytoplasm, but under certain circumstances it is translocated to the nucleus. In the nucleus, Trx has been shown to activate redox sensitive transcription factors, including NF-κβ [100]. Under normal conditions, NF-κβ is present in the cytoplasm where it is inhibited and sequestered by its physiological inhibitor, inhibitor of-κβ (Iκβ). Under oxidative stress, ROS releases Iκβ subunit from NF-κβ which is then translocated to the nucleus [101]. In the nucleus, Trx reduces Cys62 in the NF-κβ subunit p50 allowing NF-κβ to bind to the recognition site present on the promoter region of its target genes, which are involved in cellular processes including, cell growth and survival (Figure 3) [100-102]. Trx also regulates the activity of other transcription factors such as Activator protein-1 (AP-1), via Redox factor-1 (Ref-1). Trx reduces Ref-1 in the nucleus, which in turn reduces cysteine residues present in the DNA-binding domains of Fos and Jun and thus activates AP-1 (Figure 4) [103]. Using in vitro diamide-induced cross-linking study and in vivo mammalian two-hybrid assays, Trx1 was shown to directly bind to Ref-1 in the nucleus and to activate the transcriptional activity of AP-1 [104].


Cross Talk between Two Antioxidant Systems, Thioredoxin and DJ-1: Consequences for Cancer.

Raninga PV, Trapani GD, Tonissen KF - Oncoscience (2014)

Induction of Trx1 expression by DJ-1 via the Nrf2 pathwayUnder oxidative stress, DJ-1 inhibits the interaction between Nrf2 and its inhibitor Keap1 resulting in activation of Nrf2. Activated Nrf2 translocates to the nucleus and binds the ARE element in the Trx1 promoter and induces Trx1 expression. Figure adapted and used with permission from the authors [135].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4295760&req=5

Figure 4: Induction of Trx1 expression by DJ-1 via the Nrf2 pathwayUnder oxidative stress, DJ-1 inhibits the interaction between Nrf2 and its inhibitor Keap1 resulting in activation of Nrf2. Activated Nrf2 translocates to the nucleus and binds the ARE element in the Trx1 promoter and induces Trx1 expression. Figure adapted and used with permission from the authors [135].
Mentions: Trx is usually present in the cytoplasm, but under certain circumstances it is translocated to the nucleus. In the nucleus, Trx has been shown to activate redox sensitive transcription factors, including NF-κβ [100]. Under normal conditions, NF-κβ is present in the cytoplasm where it is inhibited and sequestered by its physiological inhibitor, inhibitor of-κβ (Iκβ). Under oxidative stress, ROS releases Iκβ subunit from NF-κβ which is then translocated to the nucleus [101]. In the nucleus, Trx reduces Cys62 in the NF-κβ subunit p50 allowing NF-κβ to bind to the recognition site present on the promoter region of its target genes, which are involved in cellular processes including, cell growth and survival (Figure 3) [100-102]. Trx also regulates the activity of other transcription factors such as Activator protein-1 (AP-1), via Redox factor-1 (Ref-1). Trx reduces Ref-1 in the nucleus, which in turn reduces cysteine residues present in the DNA-binding domains of Fos and Jun and thus activates AP-1 (Figure 4) [103]. Using in vitro diamide-induced cross-linking study and in vivo mammalian two-hybrid assays, Trx1 was shown to directly bind to Ref-1 in the nucleus and to activate the transcriptional activity of AP-1 [104].

Bottom Line: In response to increased ROS levels, cellular antioxidant molecules such as thioredoxin, peroxiredoxins, glutaredoxins, DJ-1, and superoxide dismutases are upregulated to counteract the detrimental effect of ROS.However, targeting one of these antioxidants alone may not be an effective anti-cancer therapy.This review focuses on the cross-talk between thioredoxin and DJ-1 and highlights the importance and consequences of targeting thioredoxin and DJ-1 together to develop an effective anti-cancer therapeutic strategy.

View Article: PubMed Central - PubMed

Affiliation: School of Biomolecular and Physical Sciences, Griffith University, Nathan, Qld, Australia ; Eskitis Institute for Drug Discovery, Griffith University, Nathan, Qld, Australia.

ABSTRACT
Oxidative stress, which is associated with an increased concentration of reactive oxygen species (ROS), is involved in the pathogenesis of numerous diseases including cancer. In response to increased ROS levels, cellular antioxidant molecules such as thioredoxin, peroxiredoxins, glutaredoxins, DJ-1, and superoxide dismutases are upregulated to counteract the detrimental effect of ROS. However, cancer cells take advantage of upregulated antioxidant molecules for protection against ROS-induced cell damage. This review focuses on two antioxidant systems, Thioredoxin and DJ-1, which are upregulated in many human cancer types, correlating with tumour proliferation, survival, and chemo-resistance. Thus, both of these antioxidant molecules serve as potential molecular targets to treat cancer. However, targeting one of these antioxidants alone may not be an effective anti-cancer therapy. Both of these antioxidant molecules are interlinked and act on similar downstream targets such as NF-κβ, PTEN, and Nrf2 to exert cytoprotection. Inhibiting either thioredoxin or DJ-1 alone may allow the other antioxidant to activate downstream signalling cascades leading to tumour cell survival and proliferation. Targeting both thioredoxin and DJ-1 in conjunction may completely shut down the antioxidant defence system regulated by these molecules. This review focuses on the cross-talk between thioredoxin and DJ-1 and highlights the importance and consequences of targeting thioredoxin and DJ-1 together to develop an effective anti-cancer therapeutic strategy.

No MeSH data available.


Related in: MedlinePlus