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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

Consequences of targeting each antioxidant, Trx1 and DJ-1, alone or in combination in cancerBoth Trx1 and DJ-1 exert cytoprotection by independent mechanisms as well as by acting on common targets such as, NF-κB and PTEN. Targeting DJ-1 alone may not be sufficient to induce cell death since Nrf2 can also be activated by other stress stimuli leading to Trx1 upregulation. Moreover, Trx1 also activates NF-κB and inhibits the tumour suppressor activity of PTEN leading to cell survival and tumour growth. Thus even after inhibition of DJ-1, all other cytoprotective machineries are functional and may promote tumour growth. Similarly, targeting Trx1 alone may not induce cancer cell death since DJ-1 may activate other Nrf2-targeted cytoprotective genes, or activates NF-κB, or inhibits tumour suppressor activity of PTEN resulting in cell survival and tumour growth. On the other hand, targeting Trx1 and DJ-1 together may completely shut down all the cytoprotective machineries regulated by these antioxidants and leads to cancer cell apoptosis. Hence, targeting two or more antioxidants in conjunction may prove an effective therapy to treat cancer.
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Figure 5: Consequences of targeting each antioxidant, Trx1 and DJ-1, alone or in combination in cancerBoth Trx1 and DJ-1 exert cytoprotection by independent mechanisms as well as by acting on common targets such as, NF-κB and PTEN. Targeting DJ-1 alone may not be sufficient to induce cell death since Nrf2 can also be activated by other stress stimuli leading to Trx1 upregulation. Moreover, Trx1 also activates NF-κB and inhibits the tumour suppressor activity of PTEN leading to cell survival and tumour growth. Thus even after inhibition of DJ-1, all other cytoprotective machineries are functional and may promote tumour growth. Similarly, targeting Trx1 alone may not induce cancer cell death since DJ-1 may activate other Nrf2-targeted cytoprotective genes, or activates NF-κB, or inhibits tumour suppressor activity of PTEN resulting in cell survival and tumour growth. On the other hand, targeting Trx1 and DJ-1 together may completely shut down all the cytoprotective machineries regulated by these antioxidants and leads to cancer cell apoptosis. Hence, targeting two or more antioxidants in conjunction may prove an effective therapy to treat cancer.

Mentions: Thus, tumours having elevated levels of antioxidants, such as Trx1 and DJ-1, may not respond well to the therapies targeting only one of them. Inhibiting either Trx1 or DJ-1 alone may allow the other to activate downstream signalling cascade leading to the tumour cell survival and proliferation. On the other hand, targeting both Trx1 and DJ-1 in conjunction may completely shut down the antioxidant defence systems regulated by these antioxidants and render the cancer cells sensitive to ROS-induced cell death. Figure 5 summarises the consequences of targeting Trx1 and DJ-1 alone or in combination in cancer cells.


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

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

Consequences of targeting each antioxidant, Trx1 and DJ-1, alone or in combination in cancerBoth Trx1 and DJ-1 exert cytoprotection by independent mechanisms as well as by acting on common targets such as, NF-κB and PTEN. Targeting DJ-1 alone may not be sufficient to induce cell death since Nrf2 can also be activated by other stress stimuli leading to Trx1 upregulation. Moreover, Trx1 also activates NF-κB and inhibits the tumour suppressor activity of PTEN leading to cell survival and tumour growth. Thus even after inhibition of DJ-1, all other cytoprotective machineries are functional and may promote tumour growth. Similarly, targeting Trx1 alone may not induce cancer cell death since DJ-1 may activate other Nrf2-targeted cytoprotective genes, or activates NF-κB, or inhibits tumour suppressor activity of PTEN resulting in cell survival and tumour growth. On the other hand, targeting Trx1 and DJ-1 together may completely shut down all the cytoprotective machineries regulated by these antioxidants and leads to cancer cell apoptosis. Hence, targeting two or more antioxidants in conjunction may prove an effective therapy to treat cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Consequences of targeting each antioxidant, Trx1 and DJ-1, alone or in combination in cancerBoth Trx1 and DJ-1 exert cytoprotection by independent mechanisms as well as by acting on common targets such as, NF-κB and PTEN. Targeting DJ-1 alone may not be sufficient to induce cell death since Nrf2 can also be activated by other stress stimuli leading to Trx1 upregulation. Moreover, Trx1 also activates NF-κB and inhibits the tumour suppressor activity of PTEN leading to cell survival and tumour growth. Thus even after inhibition of DJ-1, all other cytoprotective machineries are functional and may promote tumour growth. Similarly, targeting Trx1 alone may not induce cancer cell death since DJ-1 may activate other Nrf2-targeted cytoprotective genes, or activates NF-κB, or inhibits tumour suppressor activity of PTEN resulting in cell survival and tumour growth. On the other hand, targeting Trx1 and DJ-1 together may completely shut down all the cytoprotective machineries regulated by these antioxidants and leads to cancer cell apoptosis. Hence, targeting two or more antioxidants in conjunction may prove an effective therapy to treat cancer.
Mentions: Thus, tumours having elevated levels of antioxidants, such as Trx1 and DJ-1, may not respond well to the therapies targeting only one of them. Inhibiting either Trx1 or DJ-1 alone may allow the other to activate downstream signalling cascade leading to the tumour cell survival and proliferation. On the other hand, targeting both Trx1 and DJ-1 in conjunction may completely shut down the antioxidant defence systems regulated by these antioxidants and render the cancer cells sensitive to ROS-induced cell death. Figure 5 summarises the consequences of targeting Trx1 and DJ-1 alone or in combination in cancer cells.

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