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The Role of the Ubiquitin Proteasome System in Lymphoma

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The Role of the Ubiquitin Proteasome System in Lymphoma ONCH-1714; No. of Pages 17 ARTICLE IN PRESS Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx The role of the ubiquitin proteasome system in lymphoma a,∗ b a c K. Stephen Suh , Takemi Tanaka , Sreeja Sarojini , Ginah Nightingale , a a a Rajendra Gharbaran , Andrew Pecora , Andre Goy a John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, United States b Thomas Jefferson University, Philadelphia, PA 19107, United States c Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19130, United States Accepted 14 February 2013 Contents 1. Introduction. 00 2. Signaling pathways regulated by the UPS . 00 3. Current therapeutic options for lymphoma . 00 3.1. Class A compounds . 00 3.2. Class B compounds . 00 3.3. Class C compounds .. 00 3.4. Class D compounds . 00 3.5. Class E compounds. 00 4. Unfolded protein response (UPR) .. 00 5. Apoptosis. 00 6. Conclusion .. 00 Reviewers ... 00 References.... 00 Biographies ..... 00 Abstract The ubiquitin-proteasome system (UPS) maintains the integrity of cellular processes by controlling protein degradation pathways. The role of the UPS in proliferation, cell cycle, differentiation, DNA repair, protein folding, and apoptosis is well documented, and a wide range of protein activities in these signaling pathways can be manipulated by UPS inhibitors, which include many anti-cancer agents. Naturally occurring and synthetic drugs designed to target the UPS are currently used for hematological cancers, including lymphoma. These drugs largely interfere with the E1 and E2 regions of the 26S proteasome, blocking proteasomal activity and promoting apoptosis by enhancing activities of the extrinsic (death receptors, Trail, Fas) and intrinsic (caspases, Bax, Bcl2, p53, nuclear factor-kappa B, p27) cell death programs. This review focuses on recent clinical developments concerning UPS inhibitors, signaling pathways that are affected by down-regulation of UPS activities, and apoptotic mechanisms promoted by drugs in this class that are used to treat lymphoma. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Ubiquitin proteasome system; Lymphoma; Bortezomib; Carfilzomib; Marizomib; CEP-18770; Clinical trials-UPS inhibitors 1. Introduction The homeostasis of cellular proteins is important for ∗ Corresponding author at: The Genomics and Biomarkers Program, John maintaining the integrity and health of the cell, and active Theurer Cancer Center, Hackensack University Medical Center, 40 Prospect protein degradation by the ubiquitin-proteasome system Avenue, Hackensack, NJ 07601, United States. Tel.: +1 201 996 8214; (UPS) is the major pathway through which this cellular fax: +1 201 336 8776. E-mail address: [email protected] (K.S. Suh). balance is achieved (Fig. 1). This process is pivotal in 1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2013.02.005 Please cite this article in press as: Suh KS, et al. The role of the ubiquitin proteasome system in lymphoma. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.02.005 ONCH-1714; No. of Pages 17 ARTICLE IN PRESS 2 K.S. Suh et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx Fig. 1. Protein degradation pathway by ubiquitin-proteasome system. cell cycle control, transcriptional regulation, signal trans- inhibitors that have been developed directly target the 20S duction, antigen presentation, inflammation, ER-mediated proteasome. degradation, membrane trafficking, receptor endocytosis, The UPS plays an important role in regulating the cell apoptosis, and development [1–4]. Ubiquitin (Ub), a 76- cycle. Proteins such as cyclins A, B, D, and E, CDK inhibitor residue protein, is attached to substrate proteins via multiple p27, p21, transcription factor E2F, retinoblastoma (Rb), and adenosine-5 -triphosphate (ATP)-dependent processes by E1 tumor suppressor p53 are regulated by proteasome-mediated (Ub-activating), E2 (Ub-conjugating), and E3 (Ub-ligating) proteolysis. The blockage of cell cycle progression with pro- enzymes. These enzymes act in harmoniously coordinated teasome inhibitors is currently used against various forms of fashion via the ubiquitin moiety to achieve specific targeting cancer. NF-␬B, which participates in immune and inflam- and regulation of oligomerization, degradation, and post- matory responses, apoptosis, and cell proliferation, is also translational modification [5]. Proteasomes are abundant in regulated by the UPS. UPS-mediated protein degradation also the cytosol, and consist of multiple proteins that form the generates antigenic peptides for presentation on MHC class I 20S and 19S subcomponent complexes. Proteasomal pro- molecules [7]. Consistent with this function, the aldehyde tein degradation generally requires polyubiquitination, and class of proteasome inhibitors partly inhibits presentation ubiquitinated proteins are first recognized by the 19S cap of antigenic peptides [8]. The UPS is also manipulated complex, which unfolds the substrate in an ATP-dependent and co-opted by certain viruses, including avian leuko- process and translocates it into the proteolytic chamber of sis virus, human immunodeficiency virus type 1, simian the 20S complex to be degraded [6]. The ubiquitin conju- immunodeficiency virus, Moloney murine leukemia virus, gation cascade begins with activation of the carboxyl group and Epstein–Barr virus [9–11]. UPS is also involved in viral of Gly-76 of ubiquitin by E1. Activated ubiquitin binds to assembly; proteolytic viral maturation is inhibited upon treat- E1 and is transferred to a Cys residue of E2, which either ment of infected cells with proteasome-specific inhibitors singly or in cooperation with E3 shuttles ubiquitin to a pro- [12,13]. Proteasome inhibitors are broadly categorized into tein substrate. Subsequently, different combinations of E2 two groups (synthetic analogs and natural products), and their and E3 enzymes add a polyubiquitin chain to provide selec- structural properties and mechanisms of action have been tive tagging for degradation (Fig. 1). This process is used reviewed in detail. to degrade misfolded or aged proteins, to regulate the cell Given the importance of proteasomal protein degradation cycle through cyclin degradation, and to promote immune in various intracellular processes, inhibitors of this pathway responses through antigenic peptide processing. Thus, com- will continue to serve as both molecular probes of major ponents of the UPS pathway are attractive molecular targets cellular networks as well as potential therapeutic agents for therapeutic intervention. For a variety of reasons, most for various human diseases [14]. This review focuses on Please cite this article in press as: Suh KS, et al. The role of the ubiquitin proteasome system in lymphoma. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.02.005 ONCH-1714; No. of Pages 17 ARTICLE IN PRESS K.S. Suh et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx 3 proteasome inhibitory mechanisms that are related to the cells in vitro and in patients with one of several types of treatment of lymphoma, detailing current preclinical and clin- lymphoma [26–28]. Geminin inhibits DNA replication dur- ical developments and describing apoptotic mechanisms that ing S, G2, and M phases by preventing the incorporation of may underlie the antitumor activities of the inhibitors. MCM proteins into the prereplication complex, thus playing an important role in DNA replication licensing. Geminin ubi- quitination by the anaphase-promoting complex/cyclosome 2. Signaling pathways regulated by the UPS (APC/C) ubiquitin-protein ligase and subsequent degradation by the 26S proteasome permits DNA replication to proceed Numerous regulatory protein participants in cellular [29]. Unbalanced expression of geminin is associated with processes undergo proteolytic degradation. The UPS has B-cell lymphomagenesis [30] and genomic instability, espe- been targeted as part of the chemotherapeutic regimen cially in MCL with p53/ARF inactivation [31]. In addition, for solid tumors and hematological malignancies, such as the overexpression of geminin has been proposed to play a non-Hodgkin’s lymphoma (NHL). The roles of proteins or role in the pathology of acute leukemia [32]. molecular targets that are proteolytically degraded by the 26S Cyclins have been directly implicated in the pathogenesis proteasome of the UPS in basic cellular activities (Fig. 1), in of lymphoma. Cyclin A is required for entry into mitosis and lymphomagenesis, and in tumor progression are described S-phase progression, and is ubiquitinated and targeted for below. proteasomal degradation by APC/C during late M to early Cell cycle progression requires programmed and peri- G1 phase [33]. Bcl-1 (CCND1 and PRAD1) has been impli- odic expression and degradation of specific proteins [15]. cated in the pathogenesis of multiple types of NHL, and its Cyclins, cyclin-dependent kinases, and their inhibitors are protein product, cyclin D1, plays an important role in the target proteins degraded by the 26S proteasome in an orderly transition from G1 to S phase in response to mitogens. Over- and sequential manner to regulate the cell cycle [16]. G1/S expression of cyclin D1 shortens the G1 phase and reduces phase progression requires coordination of positive regula- the dependency of the cell on extrinsic mitogenic signals. tors (cyclins, cyclin-dependent kinases [CDKs], CDK-cyclin Defects
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