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Proteasome inhibitor PS-341 (bortezomib) induces calpain-dependent IkappaB(alpha) degradation.

ABSTRACT: The proteasome, a key component of the ubiquitin-proteasome pathway, has emerged as an important cancer therapeutic target. PS-341 (also called Bortezomib or Velcade) is the first proteasome inhibitor approved for newly diagnosed and relapsed multiple myeloma and is currently being tested in many clinical trials against other types of cancers. One proposed mechanism by which PS-341 exerts its anticancer effect is inactivation of nuclear factor-kappaB (NF-kappaB) through prevention of IkappaB(alpha) degradation. In this study, we show that PS-341 at concentrations that effectively inhibited the growth of human cancer cells, instead of increasing IkappaB(alpha) stability, paradoxically induced IkappaB(alpha) degradation. As a result, PS-341 facilitated p65 nuclear translocation and increased NF-kappaB activity. Moreover, IkappaB(alpha) degradation by PS-341 occurred early before induction of apoptosis and could not be inhibited by a pan-caspase inhibitor or caspase-8 silencing; however, it could be prevented with calpain inhibitors, calcium-chelating agents, calpain knockdown, or calpastatin overexpression. In agreement, PS-341 increased calpain activity. These data together indicate that PS-341 induces a calpain-mediated IkappaB(alpha) degradation independent of caspases. In the presence of a calpain inhibitor, the apoptosis-inducing activity of PS-341 was dramatically enhanced. Collectively, these unexpected findings suggest not only a novel paradigm regarding the relationship between proteasome inhibition and NF-kappaB activity but also a strategy to enhance the anticancer efficacy of PS-341.

SUBMITTER: Li C

PROVIDER: S-EPMC2871478 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Proteasome inhibitor PS-341 (bortezomib) induces calpain-dependent IkappaB(alpha) degradation.

Li Chunyang C Chen Shuzhen S Yue Ping P Deng Xingming X Lonial Sagar S Khuri Fadlo R FR Sun Shi-Yong SY

The Journal of biological chemistry 20100324 21

The proteasome, a key component of the ubiquitin-proteasome pathway, has emerged as an important cancer therapeutic target. PS-341 (also called Bortezomib or Velcade) is the first proteasome inhibitor approved for newly diagnosed and relapsed multiple myeloma and is currently being tested in many clinical trials against other types of cancers. One proposed mechanism by which PS-341 exerts its anticancer effect is inactivation of nuclear factor-kappaB (NF-kappaB) through prevention of IkappaB(alp ...[more]

PMID: 20335171

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Project description:Golden retriever muscular dystrophy (GRMD) is a genetic myopathy corresponding to Duchenne muscular dystrophy (DMD) in humans. Muscle atrophy is known to be associated with degradation of the dystrophin-glycoprotein complex (DGC) via the ubiquitin-proteasome pathway. In the present study, we investigated the effect of bortezomib treatment on the muscle fibers of GRMD dogs. Five GRMD dogs were examined; two were treated (TD- Treated dogs) with the proteasome inhibitor bortezomib, and three were control dogs (CD). Dogs were treated with bortezomib using the same treatment regimen used for multiple myeloma. Pharmacodynamics were evaluated by measuring the inhibition of 20S proteasome activity in whole blood after treatment and comparing it to that in CD. We performed immunohistochemical studies on muscle biopsy specimens to evaluate the rescue of dystrophin and dystrophin-associated proteins in the muscles of GRMD dogs treated with bortezomib. Skeletal tissue from TD had lower levels of connective tissue deposition and inflammatory cell infiltration than CD as determined by histology, collagen morphometry and ultrastructural analysis. The CD showed higher expression of phospho-NF?B and TGF-?1, suggesting a more pronounced activation of anti-apoptotic factors and inflammatory molecules and greater connective tissue deposition, respectively. Immunohistochemical analysis demonstrated that dystrophin was not present in the sarcoplasmic membrane of either group. However, bortezomib-TD showed higher expression of ?- and ?-dystroglycan, indicating an improved disease histopathology phenotype. Significant inhibition of 20S proteasome activity was observed 1 hour after bortezomib administration in the last cycle when the dose was higher. Proteasome inhibitors may thus improve the appearance of GRMD muscle fibers, lessen connective tissue deposition and reduce the infiltration of inflammatory cells. In addition, proteasome inhibitors may rescue some dystrophin-associated proteins in the muscle fiber membrane.

Dataset Information

Proteasome inhibitor PS-341 (bortezomib) induces calpain-dependent IkappaB(alpha) degradation.

Publications

Proteasome inhibitor PS-341 (bortezomib) induces calpain-dependent IkappaB(alpha) degradation.

Similar Datasets

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