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  • Review Article
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The proteasome: a suitable antineoplastic target

Key Points

  • The proteasome is an abundant, catalytic complex that is found in both the nucleus and cytoplasm of eukaryotic cells.

  • The function of the proteasome is to degrade or process intracellular proteins, some of which represent mediators of cell-cycle progression and apoptosis, such as the cyclins, caspases, BCL2 and nuclear factor of κB (NF-κB).

  • Malignant cells are more susceptible to certain proteasome inhibitors, which might be explained, in part, by the reversal or bypass of some of the effects of the mutations in cell-cycle and apoptotic checkpoints that have led to tumorigenesis.

  • Other explanations for this differential susceptibility include higher dependency of highly proliferative malignant cells on the proteasome system to remove aberrant proteins and the dependence of some tumours on the proteasome-dependent NF-κB activation pathway to maintain drug or radiation resistance.

  • In addition to direct apoptotic effects, there is a strong biological basis for using proteasome inhibition to enhance sensitivity to standard chemotherapy and radiation therapy, and to overcome drug resistance.

  • The proteasome inhibitor bortezomib has established clinical efficacy and an approved clinical indication for the treatment of relapsed and refractory multiple myeloma — proof of the principle that the proteasome is a suitable antineoplastic target.

Abstract

The proteasome is an abundant multi-enzyme complex that provides the main pathway for degradation of intracellular proteins in eukaryotic cells. As such, it controls the levels of proteins that are important for cell-cycle progression and apoptosis in normal and malignant cells; for example, cyclins, caspases, BCL2 and nuclear factor of κB. A proteasome inhibitor — bortezomib — has been developed that has shown efficacy as an anticancer agent in the clinic. How can targeting such a universal, broadly active cellular component provide the selectivity and specificity that are required for cancer therapeutics?

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Figure 1: Eukaryotic protein degradation.
Figure 2: Proteasome structure.
Figure 3: Cellular pathways associated with the proteasome.

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Acknowledgements

Preparation of the manuscript was supported in part by an unrestricted grant from Millennium Pharmaceuticals.

Correction: The DOI number given for this article in the May 2004 print issue of Nature Reviews Cancer was wrong. The correct DOI number is: doi:10.1038/nrc1361.

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The author derives financial benefit based on the net sales of Velcade. This is a residual benefit resulting from an investorship role while at ProScript Inc., which was ultimately aquired by Millennium Pharmaceuticals in December 1999.

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DATABASES

Cancer.gov

acute lymphoblastic leukaemia

acute myelogenous leukaemia

breast cancer

colorectal cancer

multiple-myeloma

non-Hodgkin's lymphoma

non-small-cell lung cancer

ovarian cancer

pancreatic cancer

prostate cancer

LocusLink

BCL2

caspase-3

caspase-8

CDC25A

CDC25B

CDC25C

E1

KIP1

MDR1

p53

WAF1

FURTHER INFORMATION

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Genome Knowledge Base

International Myeloma Foundation

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NCI Cancer.gov Search for Clinical Trials

Proteasome Inhibitors in Cancer by Millennium Pharmaceuticals

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Glossary

APOPTOSIS

Programmed cell death is triggered through two main pathways. One involves cell-surface death receptors (such as CD95), which activate caspase-8. The other is initiated by mitochondrial perturbations, leading to release of pro-apoptotic molecules from the intermitochondrial membrane space, which stimulates the caspase-9 proteolytic pathway.

PROTEASE

An enzyme that breaks down a protein by causing cleavage of a peptide chain at a specific position (that is, when the carbonyl group is part of a specific amino acid). Trypsin is a mammalian intestinal protease that specifically hydrolyses at lysine or arginine.

UBIQUITIN

A 76-amino-acid polypeptide that is highly conserved in eukaryotic cells.

CHYMOTRYPSIN

A mammalian intestinal protease that is specific for phenylalanine, tryptophan and tyrosine.

NUCLEOPHILE

The portion of a molecule that provides an electron pair in a reaction, ultimately causing a bond to break and the formation of a new bond.

CYCLIN

A short-lived regulatory protein that activates cyclin-dependent kinases to induce cell-cycle progression.

MDM2

An E3 ubiquitin ligase that targets p53 for degradation through the 26S proteasome. It is also a transcriptional target of p53, functioning in a negative-feedback loop.

MULTIDRUG-RESISTANCE GENE 1

A gene that responds to environmental stress by allowing the cell to develop resistance to a large number of cancer chemotherapeutic agents.

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Adams, J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4, 349–360 (2004). https://doi.org/10.1038/nrc1361

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