The role of the ubiquitin/proteasome system in cellular responses to radiation

McBride, William H.; Iwamoto, Keisuke S.; Syljuåsen, Randi G.; Pervan, Milena; Pajonk, Frank

doi:10.1038/sj.onc.1206676

Cited by 136 publications

(94 citation statements)

References 270 publications

(229 reference statements)

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“…Bortezomib, a boronic acid dipeptide derivative, is a member of a class of antitumor compounds and has recently been approved as a single agent for the therapy of multiple myeloma because of its direct growth-inhibitory and apoptotic effects on this cancer (20,21). Bortezomib has also been shown to have antitumor effects either alone or in combination with chemotherapeutic agents against numerous other tumors (22)(23)(24). We have recently demonstrated that bortezomib can sensitize both murine solid tumor and leukemia cell lines to apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (25).…”

mentioning

confidence: 99%

Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib

Sun

Panoskaltsis‐Mortari

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

233

202

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Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. Increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer

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confidence: 99%

Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib

Sun

Panoskaltsis‐Mortari

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

233

202

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“…The Ub-proteasome system is at the center of cellular proteolysis that controls numerous cellular processes including cell cycle checkpoint and DNA repair (McBride et al, 2003). It has been shown that proteasome inhibitors are able to activate cell cycle checkpoint signaling pathways at G1/S, S and G2/ M phases (Bendjennat et al, 2003;McBride et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that proteasome inhibitors are able to activate cell cycle checkpoint signaling pathways at G1/S, S and G2/ M phases (Bendjennat et al, 2003;McBride et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Human hRad1 but not hRad9 protects hHus1 from ubiquitin–proteasomal degradation

2004

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Three of the Rad family proteins, Rad9, Rad1, and Hus1, can interact with each other and form a heterotrimeric complex that is thought to play a role in the sensing step of the DNA integrity checkpoint pathways, but the nature of the Rad9-Rad1-Hus1 complex assembly remains enigmatic. Here, we demonstrate that the human hRad1 protein plays a significant role as molecular chaperone in the process of the hRad9-hRad1-hHus1 heterotrimeric complex formation. In contrast to hRad1, hHus1 is an unstable protein that is actively degraded via the ubiquitin-proteasome pathway. We show that treating cells with proteasome-specific inhibitors stabilizes hHus1 expression. Moreover, hRad1 can associate with hHus1 in the absence of hRad9 and protect hHus1 from ubiquitination and degradation in the cytoplasm. Importantly, genotoxic stress induces hRad1 expression and stabilizes the hHus1 protein. Taken together, these findings suggest a novel role of hRad1 as a potential intrinsic chaperone in the stabilization of hHus1 for the hRad9-hRad1-hHus1 checkpoint complex formation.

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“…The copper-binding activity of disulfiram may also be involved in this mode of action because the formation of organic copper complexes appears to be responsible for proapoptotic proteasome inhibition (4). Other proteasome inhibitors (13), including the reduced form of disulfiram (diethyldithiocarbamate) (14), have radiosensitizing effects, and this may also apply to disulfiram, further increasing its potential as an anticancer agent.…”

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confidence: 99%

The Role of Copper in Disulfiram-Induced Toxicity and Radiosensitization of Cancer Cells

Rae

Tesson

Babich³

et al. 2013

J Nucl Med

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Disulfiram has been used for several decades in the treatment of alcoholism. It now shows promise as an anticancer drug and radiosensitizer. Proposed mechanisms of action include the induction of oxidative stress and inhibition of proteasome activity. Our purpose was to determine the potential of disulfiram to enhance the antitumor efficacy of external-beam g-irradiation and 131 I-metaiodobenzylguanidine ( 131 I-MIBG), a radiopharmaceutical used for the therapy of neuroendocrine tumors. Methods: The role of copper in disulfiram-induced toxicity was investigated by clonogenic assay after treatment of human SK-N-BE (2c) neuroblastoma and UVW/noradrenaline transporter (NAT) glioma cells. The synergistic interaction between disulfiram and radiotherapy was evaluated by combination-index analysis. Tumor growth delay was determined in vitro using multicellular tumor spheroids and in vivo using human tumor xenografts in athymic mice. Results: Escalating the disulfiram dosage caused a biphasic reduction in the surviving fraction of clonogens. Clonogenic cell kill after treatment with disulfiram concentrations less than 4 mM was copper-dependent, whereas cytotoxicity at concentrations greater than 10 mM was caused by oxidative stress. The cytotoxic effect of disulfiram was maximal when administered with equimolar copper. Likewise, disulfiram radiosensitization of tumor cells was copper-dependent. Furthermore, disulfiram treatment enhanced the toxicity of 131 I-MIBG to spheroids and xenografts expressing the noradrenaline transporter. Conclusion: The results demonstrate that the cytotoxicity of disulfiram was copper-dependent, the molar excess of disulfiram relative to copper resulted in attenuation of disulfiram-mediated cytotoxicity, copper was required for the radiosensitizing activity of disulfiram, and copper-complexed disulfiram enhanced the efficacy not only of external-beam radiation but also of targeted radionuclide therapy in the form of 131 I-MIBG. Therefore, disulfiram may have anticancer potential in combination with radiotherapy.

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The role of the ubiquitin/proteasome system in cellular responses to radiation

Cited by 136 publications

References 270 publications

Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib

Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib

Human hRad1 but not hRad9 protects hHus1 from ubiquitin–proteasomal degradation

The Role of Copper in Disulfiram-Induced Toxicity and Radiosensitization of Cancer Cells

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