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.

• Authors: Chunyang Li, Shuzhen Chen, Ping Yue, Xingming Deng, Sagar Lonial, Fadlo R Khuri, Shi-Yong Sun
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 21 Pg. 16096-104 (May 21 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20335171 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Boronic Acids
• I-kappa B Proteins
• NFKBIA protein, human
• Protease Inhibitors
• Pyrazines
• RELA protein, human
• Transcription Factor RelA
• NF-KappaB Inhibitor alpha
• Bortezomib
• CASP8 protein, human
• Calpain
• Caspase 8

Topics

• Active Transport, Cell Nucleus (drug effects)
• Apoptosis (drug effects)
• Boronic Acids (pharmacology)
• Bortezomib
• Calpain (metabolism)
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Humans
• I-kappa B Proteins (metabolism)
• Multiple Myeloma (drug therapy, metabolism)
• NF-KappaB Inhibitor alpha
• Protease Inhibitors (pharmacology)
• Pyrazines (pharmacology)
• Transcription Factor RelA (metabolism)