Physiopathogenesis of Hematological Cancer

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The number of new discoveries related to diagnostics and therapeutics of hematological cancer is significant. These have resulted in continuous progress in fundamental knowledge about molecular and ...
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Proteasome Inhibition in Hematological Malignancies

Pp. 34-49 (16)

Guilherme Augusto Silva dos Santos

Abstract

The 26S proteasome is a large multi-subunit complex responsible for the ATP-dependent degradation of ubiquitylated proteins, a critical process for signal transduction and regulation of transcription and receptor function. In cancer, deregulation of this process may contribute to progression, drug resistance and altered immune surveillance. Proteasome inhibition (PI) cause cellular apoptosis by affecting levels of short-lived proteins, by inhibition of NFκB activity and increased activity of p53, Bax and cyclin-dependent kinase inhibitors p27 and p21. Preclinical studies showed that malignant cells are more susceptible to PI than normal cells. Although a concrete explanation for this selectivity is not available yet, one possibility is that sensitivity is linked to proliferation and/or deregulated cell cycle progression. Numerous proteasome inhibitors have been developed and the first approved, bortezomib is a boronic acid dipeptide that binds directly to the 20S proteasome and blocks its enzymatic activity.

Keywords:

26S proteasome , NFκB activity , 20S proteasome, Protein Degradation , Cellular Homeostasis, Intracellular Proteolysis, Lysosome Pathway, Ubiquitin-Proteasome System, Mammalian Proteasome, Multiple Myeloma , Bortezomib.

Affiliation:

Silva dos Santos: Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Laboratorio de Hematologia Bloco G, Av. Bandeirantes 3900, Postal Code 14048900.