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Open Journal of Hematology, 2010, 1-4

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Review Article

The Expanding Role of Proteasome-Based Therapy in the Treatment of Hematologic Malignancies

James J. Driscoll

2 Hematology-Oncology Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC, USA

,1 Roopa DeChowdhury,1 Jason Burris,1,2 Christina M. Annunziata1 1 Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Corresponding Author & Address: James J. DriscollMedical Oncology Branch, National Cancer Institute, 10 Center Drive, Building 10-Room 12N-226

Magnuson Cancer Center, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (Tel): 301-451-4401; (Fax): 301-480-6255; Email: driscollj@mail.nih.gov Published: 4th September, 2010 Accepted: 4th September, 2010 Received: 30th June, 2010 Revised: 11th August, 2010 Open Journal of Hematology, 2010, 1-4 Driscoll et al.; licensee Ross Science Publishers ROSS Open Access articles will be distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided that the original work will always be cited properly. Keywords: Proteasome, Bortezomib, Multiple Myeloma, Hematologic Malignancies

ABSTRACT

The Ubiquitin (Ub)+Proteasome pathway is the major cellular pathway for the selective degradation of nuclear and cytosolic proteins. The proteasome is the catalytic core of the Ub+Proteasome pathway and has become an intriguing new target in drug development and cancer therapy for the treatment of hematologic malignancies. Successful pharmacologic inhibition of the proteasome with the boron-containing small molecule bortezomib led to US Food and Drug Administration (FDA) approval for the treatment of multiple myeloma (MM). That clinical success has propelled tremendous interest and application of proteasome inhibition to an increasing number of hematologic malignances. Inhibition of the proteasome results in the accumulation of multi-ubiquitinated proteins that are normally degraded through the tightly regulated Ub+Proteasome pathway. Such an accumulation leads to the stabilization of numerous cellular proteins that control the cell cycle, growth, proliferation and apoptosis. It is thought that the accumulation of multi-Ub~protein conjugates leads to apoptosis although there are numerous mechanisms proposed to explain how proteasome inhibition leads to cell death. However, not all patients respond to bortezomib-based therapy and moreover, those patients that do respond inevitably develop drug resistance. In addition, the mechanism of action for bortezomib remains incompletely characterized and, thus, newer proteasome inhibitors are needed and are in clinical development. The use of the proteasome inhibitor bortezomib has been expanded successfully from MM to other hematologic malignancies that include various lymphomas, Waldenstrms macroglobulinemia, Amyloidosis and Acute Myeloid Leukemia (AML). The proteasome is a validated therapeutic target and proteasome inhibitors modulate protein stability to effect tumor cell growth control and promote programmed cell death. Targeting the Ub+Proteasome pathway offers great promise in the treatment of hematologic and eventually solid tumor malignancies.

Open Journal of Hematology OPEN ACCESS

http://rossscience.orgmailto:driscollj@mail.nih.govhttp://creativecommons.org/licenses/by/3.0http://rossscience.org/ojhmt

Open Journal of Hematology, 2010, 1-4

INTRODUCTION

In eukaryotic cells, the vast majority of cytosolic and nuclear proteins are degraded through the Ub+Proteasome pathway [1]. Proteins are targeted for degradation through the covalent ligation to Ub; a highly conserved 76 amino acid polypeptide that is covalently linked in an ATP-dependent manner to target substrates [2,3]. An ATP-dependent high molecular mass complex known as the 26S proteasome then recognizes and degrades the multi-ubiquitinated protein conjugates (Fig. 1). The Ub+Proteasome pathway controls essential cellular processes such as cell-cycle progression, signal transduction, transcriptional regulation and programmed cell death [4-7]. Importantly, the Ub+Proteasome has been linked to cancer biology since it regulates the degradation of cyclins, oncoproteins and tumor

suppressors (Fig. 2).

Intracellular protein degradation occurs in two major cellular systems that control the process of protein removal: the lysosomal and the non-lysosomal Ub+Proteasome systems. The discovery of the membrane-bound organelle, the lysosome in the 1950s was important in establishing the lysosomal pathway for protein degradation. The lysosome was first thought to be the major site of protein degradation due to the action of hydrolases such as the cathepsins. However, further studies showed that most cellular proteins are degraded in a non-lysosomal process, which led to discovery of the Ub+Proteasome system. While lysosomal protein degradation is an exciting area of interest, further discussion is beyond the scope of this review.

Figure 1: The Ubiquitin+Proteasome Pathway for Protein Degradation

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Figure 2: The Role of the Ubiquitin+Proteasome Pathway in Essential Cellular Processes

In eukaryotes, the 26S proteasome is a ~2.5-MDa structure that consists of over 30 different subunits and catalyzes the ATP-dependent degradation of nuclear and cytosolic proteins [8-12]. The 26S proteasome is a highly complex and mechanistically sophisticated proteolytic machine that recognizes, unfolds, translocates and cleaves multi-ubiquitinated proteins into peptides in a sequential dis-assembly line manner. It is reasonable that these multiple activities are enzymatically and physically linked to not only improve efficiency of proteolysis but also to prevent the escape of partially deubiquitinated or partially cleaved protein substrates (Fig. 3). This structure is found in both the cytoplasm and nucleus of all eukaryotic cells [9, 10, 16 and references therein]. The 26S proteasome consists of a barrel-shaped proteolytic core complex, known as the 20S proteasome that harbors the proteolytic activities and is capped at one or both ends by 19S regulatory complexes that fulfill multiple functions [11-17].

The 20S proteasome is a multicatalytic protease that exhibits various peptidase activities to function as the catalytic core the 26S

proteasome [21-30]. All peptidase activities for proteolytic cleavage of the protein substrate reside within the 20S structure. In mammalian tissues, the 20S proteasome is comprised of up to 14 different proteins, with each subunit represented twice. The ancestor of the eukaryotic 20S proteasome is the eubacterial and archaebacterial proteasome. The architectural characteristic of 20S proteasome is its composition of four seven-numbered rings, with two outer rings containing subunits and two central rings composed of subunits. It is apparent that the subunits serve a structural function and the subunits are responsible for the catalytic activity. These are classified as either subunits or subunits based on their similarities to the two subunits found in the 20S proteasome in the archaebacterium Thermoplasma acidophilum [21-24]. In the archaebacterial form the and subunits form four seven-membered rings that stack on top of each other to form a barrel-shaped structure [21-28]. Interestingly, during this process the number of active site subunits has been reduced to three yielding six active site subunits in the eukaryotic proteasome. In parallel, the

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rather broad amino acid specificity of the archaeal subunits has been narrowed down to three more distinct specificities, which are characterized as chymotrypsin-like, trypsin-like and peptidyl-glutamyl-peptide hydrolyzing activity, the latter

cleaving after acidic amino acids [21-24]. Numerous proteasome-interacting subunits have been described in various eukaryotic organisms [29].

Figure 3: Structural Models of the Fully Assembled 26S Proteasome

The 19S regulatory complexes function in the recognition, unfolding and translocation of multi-ubiquitinated proteins [30-36]. It is thought that these regulatory complexes facilitate entry of the unfolded Ub~conjugates into the 20S proteasome to promote degradation and also to prevent erroneous or unselective proteolysis [29-36]. Assembly of the 26S proteasome complex and the attachment of the 19S particles is chaperone-mediated and an elaborate multi-step process (Figure 3). The 19S regulatory particle of yeast, which is the most thoroughly studied version is composed of at least 17 different subunits. The 19S complex itself can be split into two different subcomplexes that are known as the base and the lid. Both subcomplexes are linked to each other through subunit Rpn10 (known as S5a in mammals) (Rpn, Regulatory Particle Non-ATPase) (10 and references therein). The base is composed

of a ring of six different ATPase subunits of the AAA-type (Rpt1 to Rpt6; Rpt, Regulatory Particle Triple A protein), which dock onto the rings on both ends of the 20S core and two additional non-ATPase subunits, Rpn1 and Rpn2. The lid is composed of eight different subunits, Rpn3 and Rpn5 to Rpn11. Rpt5/S6a, is able to bind to multi-Ub chains, implying that this subunit forms part of the mechanism by which ubiquitinylated substrates are recognized by the 26S protea

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