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The Ubiquitin-Proteasome System (UPS) and the Mechanism of Action of Bortezomib Boris Cvek* and Zdenek Dvorak Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 11, 78371 Olomouc, Czech Republic Abstract: Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. There have been almost 200 clinical trials with bortezomib, both as a single agent and in combination with other drugs, for various cancers, as listed in the US National Cancer Institute database. However, bortezomib’s mechanism of action remains elusive despite enormous progress in our knowledge of the cell biology of the ubiquitin-proteasome system (UPS) and bortezomibinduced signaling events in cancer cells. This review maps a rapidly growing and open body of research in both areas.
Keywords: Ubiquitin-proteasome system, bortezomib, mechanism of action. 1. INTRODUCTION Throughout last decade, cancer chemotherapy has largely become “targeted therapy”. The classic example of a therapeutic target is the well-known tyrosine kinase Bcr-Abl, which causes chronic myelogenous leukemia. Imatinib, a famous drug approved for disease treatment, inhibits this kinase [1]. At present, there are many key players in tumorigenesis, cancer proliferation, and metastasis that are emerging as targets for therapeutic intervention strategies including [2] cellular signal transduction pathways (e.g. receptor kinases, intracellular signaling kinases), tumor vasculature (e.g. angiogenesis and vasculature disrupting), epigenetic modulators (e.g. DNA methyltransferases and histone deacetylases), integrins, heat shock proteins, poly(ADP-ribose) polymerase, and mitotic kinases. However, one of the most surprising and attractive targets for cancer chemotherapy is the ubiquitin-proteasome (UPS) system, for which the first-in-class proteasome inhibitor bortezomib (brand name: Velcade®) is used. Bortezomib has been approved by the FDA as a first-line cancer chemotherapy for multiple myeloma since June 2008. Bortezomib, formerly known as PS-341, LDP-341, and MLM341 [3], was first reported (December 1998) to attenuate inflammation in rats through proteasomal and nuclear factor-B (NF-B) inhibition [4]. In a subsequent study (April 1999) proteasome inhibitors, including bortezomib, were a means for studying the NF-B pathway [5]. The focus of this drug shifted in an article [6] authored by Julian Adams from ProScript Inc., a biotech company started by Harvard professors A. Goldberg, T. Maniatis, M. Rosenblatt, and K. Rock in 1994 under the name Myogenics (hence, the original name MG-341 or PS-341). Adams recalled the discovery of bortezomib in an interview as follows (Myeloma Today 6 May, 2003): “Early on in its development no one believed in the molecule, or the target. It was assumed that this approach would lead to overwhelming toxicity. Many needed to be convinced. Our own employees at ProScript were skeptical, the scientific founders, the Board of Directors, all in the company. As for the outside world, it was next to impossible. David Livingston, of the Dana Farber Cancer Institute, joined our scientific board and helped me enormously in changing the views within the company. I also forged a formidable alliance with the National Cancer Institute, who was also initially skeptical, but under the guidance of Edward Sausville at the NCI, we kept building the evidence for a case to see Velcade through.” *Address correspondence to this author at the Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 11, 78371 Olomouc, Czech Republic; Tel: 420 585634901; Fax: 420 585634905; E-mail:
[email protected] 1381-6128/11 $58.00+.00
As explained by Adams et al. [6], one of the first proteasome inhibitors [7] was MG-132, a peptide aldehyde based on calpain inhibitor I [8]. However, MG-132 is not sufficiently selective for proteasome inhibition because it also inhibits cathepsin B and calpains [9-10]. The 20S proteasome as a threonine protease [11] has been shown to be efficiently targeted by dipeptidyl boronic acids [12-15]. Consequently, the average growth inhibition value of 50% for bortezomib across the entire NCI cell panel (60 cell lines derived from multiple human tumors [16]) was 7 nM. Using the NCI COMPARE algorithm [17], it was shown that bortezomib had a unique toxicity “fingerprint” among 60,000 compounds. Such results encouraged further testing in animals, and bortezomib was found to be a potent tumor suppressor in several murine tumors and human xenografts [18]. Moreover, no adverse effects of i.v. bortezomib administered were noted by Adams et al. [6], although the proteasome was significantly inhibited in the tumor and in murine white blood cells, colon, liver, muscle, and prostate. Intravenous dosing with radiolabeled [14C]bortezomib demonstrated the highest radioactivity levels 10 min after drug administration in the adrenals, the kidney cortex, the liver, the prostate, and the spleen. On the contrary, the brain, the spinal cord, eyes, and testes had levels below the limits of detection. The majority (66%) of the radiolabeled drug was excreted in bile, and the reminder was excreted in the urine. However, neither fluid contained inhibitory activity, suggesting that only metabolized bortezomib was excreted. A full toxicological evaluation of bortezomib in rodents and primates revealed the side effects of bortezomib [6]. In primates, the side effects were anorexia, emesis, and diarrhea, and all occurred in a dose-dependent manner. Among the 40 other tissues examined, modest bortezomib effects were observed in the thymus and spleen. The drug was therefore approved for phase I clinical trials in human cancer patients [18]. During the trials, patients experienced low-grade fever and/or fatigue after several cycles of bortezomib at doses of approximately 1.0 mg/m2. Low-grade diarrhea and thrombocytopenia were also observed, but were not dose limiting. The most serious adverse effect of bortezomib, which remains true today, was peripheral neuropathy. From the phase I results, four malignancies appeared to be most susceptible to proteasome inhibition: androgen-independent prostate cancer [19], non-small cell lung cancer [20], melanoma [21], and multiple myeloma [22]. A pivotal phase II trial of bortezomib was performed in relapsed and/or refractory multiple myeloma patients who had progressed after a median of six previous therapeutic regimens [23]. The incidence of grade 4 adverse events was low, and most could be managed with standard approaches. For the 202 patients involved in the trial, the median time to progression was 7 months with bortezomib treatment, as compared with 3 months with the last
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treatment before entering the trial. A positive therapeutic response to bortezomib was not influenced by the type of multiple myeloma or by the type or number of previous therapies. In May 2003, the US Food and Drug Administration granted accelerated approval for bortezomib as a third-line therapy for multiple myeloma, and a year later the European Union approved its use [24-26]. Bortezomib has subsequently been approved as a second-line [27] and a first-line1 drug for multiple myeloma treatment. Furthermore, bortezomib has been approved as a second-line therapy against mantle cell lymphoma [28]. Today, there are thousands of patients using bortezomib worldwide and hundreds of clinical trials using bortezomib for the treatment of various cancers, either as a single agent or in combination therapy. The basic principles of the UPS and proteasomal inhibition in cancer therapy were recently reviewed elsewhere [29-30]. Comprehensive knowledge of the chemical principles of the proteasome inhibition is available, for instance, in a useful study published in Chemical Reviews [31]. To avoid redundancy, this review will focus on the latest reports of the cell biology of the UPS and the mechanism of action of bortezomib. 2. UPS: MUCH MORE THAN JUST PROTEOLYSIS In his Nobel Lecture (2004), Avram Hershko explained how he and co-workers found three enzymes during the years 1970-1990, the ubiquitin-activating E1, the ubiquitin-conjugating E2 and the ubiquitin-ligating E3, that target proteins for proteasomal degradation via a chain composed of units called ubiquitin [32]. However, according to Alexander Varshavsky and colleagues, another key group in early UPS research, the role of ubiquitin is not limited to proteolysis but also includes cell cycle control, DNA repair, transcription, and other essential cellular events [33]. Today, as we increasingly understand UPS complexity, it is crucial to introduce UPS in a broader cellular context. 2.1. The Various Protein Degradation Levels For the degradation of long-lived cytosolic proteins and organelles, there is a process called autophagy (“self-eating”), which can be divided into three subtypes: chaperone-mediated autophagy, microautophagy and macroautophagy. During autophagy, which is initiated by conjugating machinery that is similar to the E1-E2-E3 ubiquitin system [34], proteins are delivered to the lysosome for degradation [35]. Intriguingly, the autophagy of membrane proteins, including diverse receptors, is ubiquitin-dependent and involves Lys-63-linked (see below) polyubiquitination (or polyubiquitylation) of proteins to be degraded [36-37]. In addition to the UPS-mediated turnover of proteins with a myriad of regulatory functions, approximately 30% of all newly synthesized proteins are defective and degraded cotranslationally or destroyed within minutes of their synthesis by the UPS [38]. This alternative process, termed endoplasmic reticulum-associated degradation (ERAD), starts when misfolded substrates are flagged by a unique glycan code that is generated by mannosidases in the ER. This signal is recognized by an E3 that is anchored in the ER membrane, and the marked protein is transported across the ER membrane to be ubiquitinated and destroyed by the proteasome [39]. Although the ERAD system focuses on defective proteins, it can have an important regulatory function as well, such as in sterol synthesis [40]. For non-native protein misfolding and aggregation, there are two cytosolic quality control compartments, the juxtanuclear quality control (JUNQ) and the insoluble protein deposit (IPOD). Misfolded and aggregated proteins are mostly ubiquitinated by the quality control machinery, which focuses them in the JUNQ, a destination where chaperones and proteasomes are concentrated in close proximity to a perinuclear ER region included in the ERAD. If the machinery needed for sorting to the JUNQ is 1
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saturated, the aggregated and potentially toxic protein species are directed to the IPOD, which seems to terminally sequester protein aggregates [41]. This opens an important question in the UPS field: in addition to the machineries mentioned above, where are the proteasomes located in the cell? Here we will only show the contour of the answer: the details can be found elsewhere [42]. Within the nucleus or the cytoplasm, proteasomes rapidly diffuse, which is in contrast to their slow, unidirectional transport from the cytoplasm to the nucleus [43]. For example, proteasome subunits are generally 12 times more abundant in the cytoplasm than in the nuclear fraction of mouse liver cells [44]. The two proteasome pools, nuclear and cytoplasmic, could equilibrate during mitosis. Moreover, there could be a difference between the subtype and the subunit composition of cytoplasmic, nuclear, and microsomal proteasomes and their specific proteolytic functions [45]. In the cytoplasm, proteasomes can be tightly associated with intermediate filaments [46], actin filaments [47-48], and myofibrils [49], or they can continuously interact with proteins destined for degradation by simple collision [43]. Nuclear proteasomes have been reported to be localized to promyelocytic leukemia (PML) nuclear bodies [50-51], nucleoplasmic speckles [52] and focal clusters throughout the nucleoplasm [53]. Under some conditions, proteasomes appear in nucleoli as well [54]; however, proteasomes are not found in nucleoli under normal conditions [55-56]. 2.2. The (Immuno)Proteasomes: Structure and Function There are various proteins in all biological kingdoms, e.g. HslV protease or RNase PH in E. coli, PNPase in S. antibioticus, and archeal or eukaryotic exosomes, which appear to have evolved in a manner that is similar to proteasomes [57]. Many authoritative reviews of the composition and functions of proteasomes have been recently published [58-60]; thus, we will present only the most important features of eukaryotic proteasomes and focus on new and ongoing research in the UPS field. 2.2.1. The Core Particles The 26S proteasome, the most common proteasome type in human organisms, is a 2.4 MDa complex composed of two multisubunit subcomplexes [61-63], a barrel-like 20S core particle (CP) and a 19S regulatory particle (RP), also termed PA700. The CP contains 2 rings at the top and bottom of the barrel and 2 rings in the middle [64]. Each ring contains three catalytically active subunits 1, 2, and 5 (see Fig. 1). The active sites of the subunits are exposed in the interior of the 20S proteasome cylinder and display different peptidase activities, i.e., caspase-like or peptidylglutamyl peptide hydrolyzing-like (1), trypsin-like (2) and chymotrypsin-like (5). A cooperative multiple chaperone system is involved in the mammalian 20S proteasome assembly pathway, which is based strictly on ordered subunit incorporation [65-68]. In mammals, a number of alternative active site subunits and the proteasome maturation protein POMP are induced during the interferon- (IFN-)-mediated immune response [69]. During de novo proteasome formation, the immunosubunits 1i or LMP2, 2i or MECL1, and 5i or LMP7 are preferentially incorporated into the CP to form immunoproteasomes (iPrs) or mixed proteasomes [70]. Additionally, IFN- also induces the synthesis of the proteasome activator PA28 subunits PA28 and PA28 (see below), transporters of peptides to the ER, and a small set of aminopeptidases. The half-life of the iPrs is considerably shorter (21 hours) than that observed for the constitutive proteasomes (120 hours), and this permits cells to rapidly return to a normal state [71]. Interestingly, after IFN- stimulation, the 7 subunits are dephosphorylated, and thus, the 26S iPrs are destabilized, resulting in an increase of PA28-containing proteasome complexes [72]. Generally, IFN--induced iPrs are involved in antigen processing; however, their major function is largely an open question [73]. Immune surveillance by CD8+ T cells requires cells to display 8-10 amino
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Fig. (1). The proteasomes and their composition: structure of the 20S core particle (A) and the 19S regulatory particle (B); various kinds of the proteasomes in the cell (C).
acids long peptides bound to major histocompatibility complex class I (MHC I) molecules on their surface. Infected or cancerous cells exhibit new peptides derived from microbial/viral or mutated self-proteins, respectively, and they are subsequently recognized by CD8+ T cells and eliminated. The peptides are the products of a multifaceted process in the cytoplasm where the proteasomes, tripeptidyl peptidase II and other proteases degrade proteins into a mixture of peptides of variable lengths [74] that need to be further edited and customized before they yield peptide-MHC I complexes [75]. The cytotoxic T cell response to pathogens is generally directed against a number of immunodominant epitopes, while other potential epitopes are subdominant or not used at all. The iPrs, but not the constitutive proteasomes, are able to determine the subdominance of epitopes and shape the epitope hierarchy of cytotoxic T lymphocytes in vivo [76-79]. This could be the reason why viral infection tends to down-regulate iPr subunits under some circumstances [80]. Moreover, the role of the iPrs could be tissue-specific [81]; for instance, they seem to be involved in mouse susceptibility to Coxsackie virus myocarditis [82-83] and may have yet unresolved functions in T cell proliferation [84]. In addition to constitutive proteasomes and iPrs, there are unique proteasomes (thymoproteasomes) in both mouse and human cortical thymic epithelial cells. Thymoproteasomes have a novel catalytic subunit, 5t, with unusual enzymatic activity, and consequently, they are capable of presenting a set of self-peptides that are not seen in other cells and are required for positive CD8+ T cell selection [85-87]. 2.2.2. The Regulatory Particles Eukaryotic cells contain various regulatory complexes that bind directly to the outer rings (Fig. 1) of the 20S proteasome (ATPindependent 20S regulators PA28, PA200, and ATP-dependent 20S
regulator PA700) or reversibly bind to proteins whose proteasomal content is variable and often substoichiometric [88]. In contrast to PA700, the ATP-independent regulators do not bind to polyubiquitin chains. Mammals have three homologous PA28 (REG or 11S regulator) genes: PA28, PA28, and PA28. The first two are involved in IFN--induced proteasome assembly and create a heteromeric complex, whereas PA28 forms a homoheptamer. Mice with disrupted PA28 and PA28 genes have defective production of certain MHC I antigens, although nonimmunological functions of both activators also seem likely because of their wide expression and regulation under many physiological conditions [89]. Recent studies have revealed [90-92] a role of PA28 in ubiquitin-independent degradation of steroid receptor coactivator-3 and p21. However, the polymer form of PA28, interacts with p53 to promote its ubiquitination and proteasomal degradation [93]. Furthermore, proteasome-PA28 complexes are regulators of nuclear speckles [94], maintain chromosomal stability [95], and interact with the PML and a DNA damage checkpoint kinase [96]. PA200 is a nuclear protein that, following association with the 20S proteasome, enhances peptide hydrolysis after acidic residues in vitro [97-99]. In response to ionizing radiation, PA200 forms hybrid proteasomes with the 19S cap and the CP that accumulate on chromatin, resulting in increased proteolytic activity [100]. According to the same study, PA200-knockdown cells show genomic instability and reduced survival after exposure to ionizing radiation. Although proteasome configurations are highly dynamic [101], the 26 proteasome (19S/PA700 RP attached at both CP -rings, Fig. 1) remains intact during protein degradation [102]. The RP of the 26S proteasome contains six different AAA+ ATPase subunits (Rpt1-6 in yeast), which are combined with four non-ATPase
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subunits (Rpn1-2, Rpn10, and Rpn13 in yeast) called the base. Rpn1 and Rpn2 form toroids, thereby physically linking the site of substrate recruitment to the site of proteolysis, as Rpn1 is stacked on Rpn2 and coupled with the CP -ring [103]. The base assembly is a rapid and orchestrated process [104-110] in which there is an opening of the gate upon ATP binding to the ATPases [111] into the CP to allow for substrate entry [112]. In contrast to the ATP binding implicated in the base assembly and the proteasome activation, ATP hydrolysis is used for 26S proteasome-dependent degradation of polyubiquitinated proteins (i.e. unfolding of substrate proteins) [113]. Not surprisingly, the function of the ATPases and the gating of the 26S proteasome are variably modulated [114-115]. The second part of the 19S RP (Fig. 1) is composed of nine non-ATPase subunits (Rpn3, Rpn5-9, Rpn11-12, and Sem1 in yeast) and is called the lid [116]. The major activity of the lid is the deubiquitination of ubiquitinated proteins by the Jab1 MPN domain metalloenzyme (JAMM) domain deubiquitinase Rpn11 (Poh1 in humans) [117-118]. The lid subunits share substantial sequence homology with the COP9 signalosome (CSN), which has been proposed to be an alternative lid of the 26S proteasome [119-120]. 2.2.3. Protein Degradation by the Proteasomes Although the proteasomes are responsible for the majority of non-lysosomal protein degradation, not all eukaryotic proteins degraded by the proteasome require ubiquitination as a flag to be recognized and digested [121]. Approximately 20% of all proteins in human cells are cleaved by the 20S or 26S proteasomes in a ubiquitin-independent fashion. Such proteins contain disordered regions that likely constitute the universal structural signal for their proteolysis [122]. The well-known examples include oxidized proteins [123-124], antizyme-1-dependent degradation of ornithine decarboxylase [125], and diubiquitin (FAT10)-flagged substrates [126-127]. Interestingly, some proteins, including p53, c-Fos, and Fra-1, are known to be degraded by both ubiquitin-dependent as well as ubiquitin-independent methods [128-129]. However, most proteins require polyubiquitin chains (polyUb) as a flag to be identified for processing by the proteasome (Fig. 2) [130]. The most important type of polyUb involved in protein degradation is linked through lysine 48 of each ubiquitin molecule (K48-linked polyUb). Nonetheless, there are a variety of ubiquitin chains, even those that are heterogenous, and they are sufficient for proteasomal substrate degradation [131-134]. Moreover, the chain can be modified and switched from a K63-linked to a K48-linked polyUb flag [135]. Still, the degradation signal may be just a multiple monoubiquitination and not necessarily a chain [136]. The ubiquitin flag is recognized and bound to the 26S proteasome (Fig. 2) by specific proteins, among which five are confirmed ubiquitin receptors (two proteasome subunits of Rpn10 with Rpn13 and three shuttle factors, Rad23, Dsk2, and Ddi1) [137-139], and others have been suggested to play such a role as well (Rpt5/S6´, Rpt1, and Rpn1) [140-141]. It was hypothesized that Rpt5 “serves as a central conduit that gathers together substrates delivered by different receptor pathways” [142]. After binding, the ubiquitin chain can be remodeled by ATP-independent deubiquitinases to allow the 26S proteasome to actively regulate the substrate commitment to degradation [143-145]. Moreover, such deubiquitinating activity, which spares ubiquitin from proteasomal degradation, is enhanced by ubiquitin deficiency within the cell [146]. In contrast, the polyubiquitinated substrate attached to the 19S RP facilitates active site access and accelerates its own degradation by the 26S proteasome [147]. Subsequently, the substrate is deubiquitinated en bloc by Poh1 (Fig. 2), and the polyubiquitin chains are cleared from the binding sites on the proteasome by other deubiquitinases [148]. However, there is an exception; monoubiquitinated substrates undergo degradation together with the ubiquitin [149-150]. Compared with K48-linked polyUb chains, cellular K63-linked polyUb chains have less proteasomal accessibility, and proteasome-bound K63
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chains are more rapidly deubiquitinated, which could cause inefficient degradation of K63 conjugates [151]. The unfolding [152] and degradation of previously polyubiquitinated substrate (Fig. 2) begins at an initiation site which is usually an unstructured region of the substrate [153-154]. In cases where substrate unfolding or its translocation into the CP is not the ratelimiting step, the substrate is stored in both antechambers ( rings) while the degradation is carried out within the catalytic chamber ( rings) [155]. It seems that ongoing protein degradation may enhance 26S proteasome stability and proteolysis processivity [156]. Moreover, the CP can bind two substrates, presumably one in each antechamber, to speed up their degradation [157]. The processive cleavage of the substrates continues until the products are suitably small enough to diffuse out through the axial gates [158-159] that are opened by hydrophobic peptides [160]. The human 26S and 20S proteasomes generate different pools of fragments with a similar average length [161]. These peptides are further trimmed by other peptidases into amino acids that are reusable for new protein synthesis [162] or used for antigen processing (see above). The substrate may not be completly degraded (Fig. 2). In fact, some key transcription factors, particularly NF-B proteins, are activated by the 26S proteasome in a process called regulated ubiquitin/proteasome-dependent processing [163]. Incomplete substrate digestion seems to occur due to the presence of tightly folded domains that are cleavage-resistant and/or have stretches of sequences that do not allow unfolding [164-165]. 2.2.4. Nuclear Roles of the Proteasomes In the nucleus, there are various UPS-dependent events [166] ranging from gene expression [167-168] or translation [169-170] to DNA repair [171] to protein quality control [172]. Although UPSmediated turnover is not a general requirement for function of transactivators [173], the UPS has an intrinsic role in both of the proposed general models of their modulation [174]. In yeast, the proteasome components are widely associated with chromatin [175] and interact with RNA polymerase at multiple genomic sites [176]. Moreover, the 26S proteasome silences nonspecific transcription and keeps tissue-specific genes in a transcriptionally competent state in embryonic stem cells [177]. The 19S RP and the 20S CP alter glucocorticoid and estrogen receptor-mediated transcription in the MCF-7 breast cancer cell line [178-179]. However, the 19S RP seems to be more involved in gene expression, e.g., it has critical roles in thyroid hormone receptor-mediated transactivation [180], and proteasome ATPases can either enhance transcription [181182] or actively destabilize activator-promoter complexes [183]. The ATPases are also associated with both ribosomal DNA promoters and coding regions [184]. Furthermore, Tat-binding protein1, an ATPase of the 19S RP, is able to directly bind the androgen receptor and alter its transcriptional function [185]. Another RPassociated ATPase, TRIP1 (also known as Sug1), positively regulates the transcription of major histocompatibility complex class II [186-187]. In DNA damage signaling, the UPS is responsible for degradation of mediator of DNA damage checkpoint protein 1 (MDC1), efficient assembly of BRCA1 (breast cancer 1) foci [188], and regulated histone proteolysis [189]. 2.2.5. Health Defects from Proteasome Dysfunction The proteasome is a key player in many therapeutically interesting processes such as the hypoxia response, inflammation, neurodegeneration, muscle wasting, viral infection, and carcinogenesis [190-191]. The UPS is broadly impaired in Huntington’s disease [192-193]. Under some circumstances, UPS impairment is possibly compensated by autophagy [194]. The inhibition of the 26S proteasome by misfolded prions is the reason for their neurotoxicity [195]. Thus, it is not surprising that bortezomib is able to induce peripheral neuropathy in patients. Moreover, the accumulation of non-functional proteins is linked to atherosclerosis [196], and in
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Fig. (2). Various ways of protein recognition and degradation by the proteasome.
cotrast, proteasome inhibition could be an effective stroke therapy [197]. The 26S proteasome was also shown to regulate the human immunodeficiency virus-1 (HIV-1) promoter in both a proteolytic and non-proteolytic manner [198]. Because the activity of the UPS decreases with age, UPS dysfunction may also be a signs of aging [199]. The UPS is required for essential functions in human monocyte-derived dendritic cells [200], and as well as it is a key factor in mammalian stem and progenitor cells [201]. 2.3. The (de)Ubiquitination Machinery The basic information on ubiquitin and ubiquitination is available in many specialized reviews [202-204]. A protein destined for degradation is recognized by an E3 ligase due to a specific degradation signal or “degron” [205]. Polyubiquitination is achieved when the E3 ligase binds to both the substrate and an E2 enzyme that carries a ubiquitin molecule (Fig. 2). A ubiquitin is transferred to the substrate (the first ubiquitin) or to the substrate-bound ubiquitin chain to extend it. The ubiquitin-free E2 is substituted with a new ubiquitin-loaded E2 using a unique E1 enzyme and ubiquitination continues on to the next step; the chain is longer by one ubiquitin. However, this “canonical view” is now being modified by new discoveries. For example, recent data suggest there is only one E1 in human cells but at least two, Uba6 and Ube1, which charge different E2 cohorts [206-207]. It appears there are ubiquitin chain elongation factors, termed E4 enzymes, that are required in some cases with the E1-E2-E3 cascade for efficient ubiquitination [208]. In yeast, an AAA+ ATPase prevents the formation of excessive and useless multiubiquitin chains [209]. It was also reported that ubiquitin oligomers, which
are possibly extended by an E1 enzyme itself on an E2 enzyme [210], can directly relocate from E2 enzymes to a substrate [211]. Some E2 enzymes seem to be specific for monoubiquitination, and others are specific for chain assembly on preattached ubiquitin [212-213]. An E2 enzyme is capable of polyubiquitinating and targeting itself for proteasomal degradation by a novel mechanism [214]. In humans, there are hundreds of E3 enzymes. The two major types of human E3 ligases are defined by the presence of either a homologous to E6-associated protein C-terminus (HECT) or a really interesting new gene (RING) domain (Fig. 2) [215-216]. E3 ligases are involved in many cellular events such as oscillation of the circadian clock [217-219], nuclear processes [220], mitosis [221], and longevity in response to diet restriction [222]. In addition to K48- and K63-linked chains (see above), there are many other types of ubiquitin linkages, including K6-, K11-, K27-, K29-, and K33-linked chains; mixed linkages in which two different bonds at one ubiquitin molecule are formed and thus the chain is forked; and heterologous linkages in which ubiquitin forms chains with ubiquitin-like [223] proteins chains [224]. Some ubiquitination mechanisms lead to nondegradable forked ubiquitin chains that contain many types of linkages [225-226]. Ubiquitin has many nonproteolytic functions in cell signaling [227-228], and those that are particularly well described include those for gene expression, NF-B pathway activation, and the DNA damage response [229-235]. Ubiquitination and deubiquitination also have multiple roles in cell cycle progression and control [236238]. The structure, activity, and function of known deubiquitinases (DUBs, Fig. 2) have been summarized in current reviews [239-
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242]. DUBs are divided into five families: 1. ubiquitin C-terminal hydrolases (UCHs), 2. ubiquitin-specific proteases (USPs), 3. Machado-Joseph disease protein domain proteases (MJDs), 4. ovarian tumor proteases (OTUs), and 5. JAMM motif proteases. The first four of these DUB families encode papain-like thiol proteases, and JAMM domain DUBs encode metalloproteases with a zinc atom in their active site. To date, 774 candidate interacting proteins associated with 75 DUBs have been identified [243]. According to the same study, DUBs funtion in protein turnover, transcription, RNA processing, DNA damage, and ERAD. As a therapeutic target in oncology, the JAMM domain DUB Poh1 seems to be an interesting target, as it is vital for 26S proteasome function [244]. However, future JAMM domain inhibitors would likely target other JAMM DUBs that are involved in various cellular processes such as deneddylation [245-246] and deubiquitination of K63-linked polyUb chains [247-248]. 3. 20S PROTEASOME INHIBITION: BORTEZOMIB’S MECHANISM OF ACTION Until 2010, there was no clear answer, at cellular level, for why the inhibition of proteasomes is a successful anticancer strategy. However, taking into consideration the multiple functions of proteasomes, it is clear that such pertubartion of a cell, whether cancerous or normal, must lead to multiple sequelae [249-251]. Bortezomib could also have proteasome-unrelated targets within the cell [252]. Therefore, it is not surprising that various cell lines could profoundly differ in their response to a proteasome inhibitor [253255]. For example, the downregulation of Akt signaling seems to be a major molecular determinant of bortezomib-induced apoptosis in hepatocellular carcinoma cells [256]; however, bortezomib activates pro-survival Akt in prostate cancer [257]. Cells expressing lower proteasome levels are significantly more vulnerable to a proteasome inhibitor [258]. Moreover, diverse proteasome inhibitors have assorted inhibitory effects on a variety of proteasome subtypes [259]. Interestingly, and in contrast to tumor tissues and hypertrophically growing postmitotic cells [260], healthy cells are less sensitive to proteasome inhibition (e.g., bortezomib is used in Table 1.
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the clinic) [261]. Possible reasons for this are listed below [262]. First: Proteasome inhibitors are known for their ability to block the tumorigenic NF-B pathway; hence, they both suppress cancer and sensitize tumors to other anticancer drugs [263]. Growing evidence from recent years, however, paints a much more complex picture. Second: As cell cycle checkpoints are disrupted in cancer cells, the cells could depend more strongly on proteasome-mediated degradation of cell cycle regulators, particularly p21 and p27 [264]. A dysregulated cell cycle likely makes cancer cells more susceptible to most proapoptotic stimuli (e.g., p53). Some of the transcriptional regulators controlling cell cycle progression (e.g. the c-MYC oncogene) are turned on in cancer cells and may be responsible for proteasome inhibition-induced cell death. The increased protein synthesis requirement in cancer cells could result in a fatal protein aggregation during the inhibition of the proteasome [265-266]. Based on recent studies cited below, we propose a key role of the proapoptotic protein NOXA in bortezomib-mediated toxicity in most cancer cell lines (Table 1, Fig. 3). Third: In the human body, the immune and intercellular context may substantially influence the mechanism of action of bortezomib. Many cell-cell interactions were reported to be altered by proteasomal inhibition in vivo (see below). 3.1. NF-B: The Suspect Lost on the Pathway For more than 20 years, the understanding of NF-B proteins, which function as transcription factors, has become increasingly more complex [267]. In contrast to the “alternative” NF-B signaling pathway, the “canonical” or “classical” pathway is better understood and employs p50:p65 heterodimer as the transcription factor. There is substantial and compelling evidence in support of the tumorigenic activity of p50:p65 NF-B: it induces anti-apoptotic genes, it produces growth and angiogenesis factors, and it directly stimulates cell-cycle progression [268]. According to recent findings, p50:p65 NF-B is necessary for inflammation-triggered migration, invasion, and metastasis of tumor cells [269]. Because the
Bortezomib Mechanism(s) of Action: Key Proteins. Cancer
Key Proteins Published
multiple myeloma
JNK, AP-1, c-MYC, p53, Bik, synergism with TRAIL
mantle cell lymphoma
p53-independent NOXA, ATF3, ATF4
cutaneous T-cell lymphoma
p53-independent NOXA
melanoma
p53-independent NOXA, c-MYC
non-small cell lung
p53-independent NOXA, Bik, JNK, p21, synergism with TRAIL
esophageal squamous cell
p53-independent NOXA
hepatocellular carcinoma
JNK, p21, synergism with TRAIL
cervix adenocarcinoma
p53-independent NOXA, ATF3, ATF4
chronic lymphocytic leukemia
p53-independent NOXA
bladder
p21, synergism with TRAIL
prostate
p21, synergism with TRAIL
Ewing’s sarcoma
p27, p21, synergism with TRAIL
glioma
synergism with TRAIL
head&neck squamous cell
Bik, Bim
The Ubiquitin-Proteasome System (UPS)
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7
Fig. (3). A map of main bortezomib mechanisms of action in various cancers in vitro: Is NOXA the key?
26S proteasome is needed for p50:p65 nuclear translocation through cleavage of the p50:p65 inhibitor IB, proteasome inhibitors suppress canonical NF-B signaling in various cancers [270274]. However, the function of bortezomib on this pathway is more complex than simply blocking it, and the network dynamics of NFB pathway [275] as well as the intracellular pharmacokinetics of bortezomib are just beginning to be understood [276]. The NF-B pathway is complex, and it is able to suppress tumorigenesis as well [277-278]. It has previously been shown that NF-B essential modulator (NEMO)-mediated NF-B activation prevents spontaneous development of hepatocellular cancer in mouse liver parenchymal cells [279]. Additionally, bortezomib is frequently unable to inhibit p50:p65 NF-B in primary multiple myeloma [280] and mantle cell lymphoma [281], and there are emerging p50:p65 NF-B pathways that are proteasomeindependent or even inducible by proteasome inhibition [282]. Proteasome inhibitors activate pro-survival p50:p65 NF-B in colon cancer or hepatic cancer cells by triggering IB degradation [283284] and in multiple myeloma cells by downregulation of IB expression [285]. Thus, NF-B inhibitors could potentiate the anticancer activity of bortezomib in general. 3.2. The Cellular Responses: NOXA is Almost Everywhere According to two key publications [286-287], the apoptotic mechanism induced by bortezomib may involve three major lines in multiple myeloma cells: 1. the mitochondrial axis, 2. the c-Jun Nterminal kinase (JNK) axis, and 3. the DNA-damage axis. Because the results of the two studies do not seem fully consistent with each
other, one can speculate that bortezomib may not activate the same pathways even in multiple myeloma. However, effects similar to those in multiple myeloma were observed in medullary and anaplastic thyroid carcinoma cells [288], which is in contrast to head and neck and pancreatic cancer cell lines, where JNK appears to counteract the anticancer effects of bortezomib [289-290]. Moreover, JNK is not the only bortezomib-induced pro-survival protein. In HepG2 hepatocellular carcinoma cells, bortezomib stimulates the accumulation of heat schock protein Hsp72, which functions to prevent HepG2 cell death [291]. The mitochondrial axis is crucial for bortezomib-induced apoptosis in many cell lines (Table 1). The proapoptotic Bcl-2 protein family member NOXA, which is Latin for damage (Fig. 3), is responsible for the sensitivity of melanoma cells, versus normal melanocytes, to bortezomib [292-294]. Hypoxia-inducible factor1, E2F-1, and p53, which are key proteasome targets with binding sites in the NOXA promoter, are not essential in ultimately defining the expression of NOXA. Instead, it has been reported that the Myc protein critically impacts NOXA transcription under proteasome inhibition (Fig. 3) [295]. However, in multiple myeloma cells, NOXA-mediated apoptosis seems to be induced by cleavage of myeloid cell leukemia-1 protein (Mcl-1, Fig. 3) [296-297]. The central role of p53-independent NOXA in bortezomib antitumor activity was confirmed in mantle cell lymphoma [298], non-small cell lung cancer [299-300], esophageal squamous cell carcinoma [301], chronic lymphocytic leukemia [302], cutaneous T-cell lymphoma, and adult T-cell leukemia/lymphoma [303]. In addition, MG-132 has also been reported to induce p53-independent apopto-
8 Current Pharmaceutical Design, 2011, Vol. 17, No. 00
sis through NOXA upregulation in chondrogenic and osteosarcoma cell lines [304]. However, there is yet another activity of the 20S proteasome inhibitors within the mitochondrial axis: they evoke a transient release of Ca2+ stores in multiple myeloma cells and mouse neurons, leading to mitochondrial Ca2+ influx and cell death [305-306]. This effect of 20S proteasome inhibition could be linked to the ability of proteasome inhibitors to cause the accumulation or upregulation of the Bik/Bim proteins in cancer cells [307-308]. If Bik is upregulated by bortezomib, it mediates calcium release and mitochondrial fragmentation [309] by possibly synergizing with NOXA (Fig. 3). Even the “guardian of the genome” p53, which is traditionally linked to the DNA damage response, may translocate to the mitochondria and induce outer membrane permeabilization. In the cytoplasm, p53 is sequestered by antiapoptotic Bcl2 proteins. A target of nuclear p53, p53 upregulated modulator of apoptosis (PUMA), functions to disrupt this interaction and release p53 to target the mitochondria [310]. Indeed, p53 activation and transcriptional induction of its target gene PUMA were shown to play a key role in the sensitivity of neuroblastoma cells and colon cancer cells to proteasome inhibitors [311-312]. The status of p53 also plays a crucial role in the response of B lymphomas to proteasome inhibition [313]. Moreover, bortezomib stabilizes a functional, nonphosphorylated p53 that is induced by proteasomal inhibition in prostate cancer cells [314]. Although bortezomib upregulates p53 in non-small cell lung cancer cells, the anticancer effects of bortezomib seem to be rather dependent on the JNK/AP-1 pathway [315]. JNK/AP-1 and p21 have also been suggested to mediate the sensitivity to bortezomib in hepatocellular carcinoma cells [316317]. In contrast, bortezomib-induced apoptosis was markedly enhanced in p21-knockout colon cancer cells [318]. It was also shown that bortezomib triggers apoptosis in multiple myeloma cells through caspase-2 activation, which is associated with ER stress and is required for the release of cytochrome c, the breakdown of mitochondrial transmembrane potential, and its downstream caspase-9 activation [319]. Because the accumulation of unfolded proteins induces ER stress, multiple myeloma cells with higher amounts of immunoglobulin subunits are more sensitive to 20S proteasome inhibition [320-322]. The bortezomibinduced ER stress is also responsible for apoptosis in pancreatic cancer cells [323] and general hypersensitivity of hypoxic tumor cells to the 20S proteasome inhibitors [324]. In squamous cell carcinoma cells, bortezomib-induced ER stress mediates apoptosis through the transcription factor ATF4 and NOXA upregulation [325]. Another study clearly demonstrated that, in various cancer cells, bortezomib activates transcription factors ATF3 and ATF4, which form a complex that is capable of binding to the NOXA promoter and triggering NOXA transcription (Fig. 3) [326]. According to a most recent report, there are 100 genes, including cMYC and NOXA, whose knockdown affects lethality in response to bortezomib and other proteasome inhibitors [327]. At the nuclear level, 20S proteasome inhibition by MG-132 and -lactacystin suppresses homologous recombination, which is indispensable for DNA double-strand break repair [328]. The suppressive effect of 20S proteasome inhibitors on homologous recombination provides us with another explanation for their strong antitumor effect. Still, bortezomib and MG-132 induce an inhibition of the general DNA damage response and the Fanconi anemia pathway at multiple levels, leading to the persistence of DNA damage and abrogation of the G1-S cell cycle checkpoint [329]. The 20S proteasome inhibitors MG-132, lactacystin, and MG-262 inhibit UV-induced translesion replication in a wide range of cancer cell lines regardless of cell origin, histological type, or p53 status; however, these inhibitors have little or no influence on normal fibroblasts or on a normal liver mesenchymal cell line [330]. In general, the mechanism of p53-independent DNA-damage-
Cvek and Dvorak
mediated apoptosis once again involves NOXA upregulation (Fig. 3) [331]. Nevertheless, further nuclear consequences of 20S proteasome inhibition could be anticipated with bortezomib-induced topoisomerase II stabilization and repression of hypoxia-inducible factor-1 (HIF-1) transcriptional activity, as previously reported [332-335]. 3.3. Immunity and Intercellular Context The anticancer activity of bortezomib could also be explained as the sensitization of the cancer cells to the immune system of the body. Some cells in the immune system express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which plays a role in both T-cell and natural killer cell-mediated tumor surveillances. Thus, TRAIL selectively induces apoptosis in a variety of tumor cells, in contrast to most normal cells [336]. However, several tumors evade TRAIL-induced apoptosis and acquire TRAIL resistance via different mechanisms. Generally, chemotherapy and radiotherapy enhance TRAIL sensitivity or reverses TRAIL resistance by regulating the downstream effectors. Because TRAIL seems to trigger mitochondrial apoptotic pathways [337], 20S proteasome inhibition should synergize with TRAIL (Tab. 1, Fig. 3). In an overnight assay, bortezomib and TRAIL were much more effective than either agent alone in promoting the apoptosis of murine myeloid leukemia and renal cancer cells [338]. Synergistic apoptotic induction occurred in prostate and bladder cancer cells, non–small cell lung cancer cells, Ewing’s sarcoma cells and primary astrocytoma cells treated with both agents [339-342]. Furthermore, bortezomib sensitizes hepatocellular carcinoma cells, but not primary human hepatocytes, to TRAIL [343-344]. Bortezomibresistant multiple myeloma cells become bortezomib-sensitive when co-treated with TRAIL [345]. Taking these data together, it is not surprising that proteasome inhibition has been shown to induce apoptosis in various cancer cells via the TRAIL death receptors DR4 and DR5 (Fig. 3), which in this way mimic the immune response [346-348]. When mice with metastatic mammary tumors were treated with bortezomib and a DR5 agonist, the median survival increased from 42 days with bortezomib alone to 180 days with both agents [349]. However, DR5 seems to be dispensable for the synergism between TRAIL and 20S proteasome inhibitors in colon cancer and prostate cancer cells [350-351]. Additionally, bortezomib overcomes TRAIL resistance in hepatocellular carcinoma cells in part through the inhibition of the Akt pathway [352]. It has been shown that natural killer cell-mediated antitumor effects can be augmented by bortezomib in mice [353], and 20S proteasome inhibition can sensitize melanoma to the lytic effects of dendritic cell-activated immune effector cells [354]. Although bortezomib sensitized breast cancer cell lines to natural killer cellmediated cell death in vitro, it failed to do so in vivo [355]. According to recent data, depletion of regulatory T cells enhances bortezomib-induced tumor sensitization to autologous natural killer cells in mice [356]. In dendritic cells (DCs), bortezomib exerts immunomodulatory effects as it reduces their phagocytic capacity, cytokine production, and immunostimulatory capacity and suppresses their phenotypic maturation [357]. In in vitro studies, bortezomib induced apoptotic cell death in immature DCs and, to a much lesser extent, in mature DCs [358]. Moreover, bortezomib was toxic for both immature and mature monocyte-derived DCs [359]. In part, bortezomib may suppress cancer by altering other cells. It interferes with angiogenesis by a direct effect on multiple myeloma patient-derived endothelial cells and their functions associated with angiogenesis [360]. Bortezomib also inhibits cell-cell adhesion and cell migration [361] and overcomes cell adhesion-mediated drug resistance [362] in vitro. Furthermore, myeloma cells within the bone marrow microenvironment exhibit an enhanced response to bortezomib [363], suggesting an important role for surrounding tissues in the sensitivity of cancer cells to bortezomib. Because multiple myeloma is a plasma cell malignancy that is characterized
The Ubiquitin-Proteasome System (UPS)
by a high capacity to induce osteolytic bone lesions [364], it is important to mention that bortezomib increases osteoblast differentiation in human mesenchymal cells without affecting the number of osteoblast progenitors or the viability of mature osteoblasts [365]. This appears to be confirmed by experiments performed in mice [366-367] and in clinical studies [368]. Given the similarities between the molecular events involved in the formation phase of the bone remodeling cycle and the induction of anagen in the hair cycle, it is not surprising that proteasome inhibitors are able to stimulate hair growth in humans [369]. 4. CONCLUDING REMARKS As our knowledge of the UPS is becoming increasingly complex, we should question simplistic models of the mechanism of action of bortezomib. It seems that inhibiting the proteasome has various consequences in different cancer tissues, thus explaining why the efficacy of bortezomib varies depending on the type of cancer. We need to understand what cellular events are triggered by bortezomib to suppress tumors in patients. The in vitro studies that demonstrate bortezomib efficacy in many solid tumors are rather confusing. Phase II clinical trials using bortezomib have failed in many solid cancers [370-379], suggesting that proteasome inhibition might target only blood cancers, e.g. multiple myeloma (clinically approved), mantle cell lymphoma (clinically approved), cutaneous T-cell lymphoma [380], mucosa-associated lymphoid tissue (MALT) lymphoma [381], and Waldenström’s macroglobulinemia [382-384]. Whether such blood cancer specifity is significant only for bortezomib or for all proteasome inhibitors will hopefully be uncovered in ongoing and future clinical trials [385]. ACKNOWLEDGEMENT This work was financed by the Czech Science Foundation (Grant No. 303/08/P137 and Grant No. 304/10/0149). ABBREVIATIONS AAA+ = AP-1 ATF
= =
Bcl2 Bik Bim
= = =
BRCA1 CD CP CSN DC DR4/DR5 DUB E1 E2 E3 E4 eIF2
= = = = = = = = = = = =
ER ERAD
= =
FADD
=
ATPases associated with diverse cellular activities Activator protein 1 Cyclic AMP-dependent transcription factor B-cell lymphoma 2 B-cell lymphoma 2-interacting killer One of B-cell lymphoma 2-interacting proteins Breast cancer 1 Cluster of differentiation Core particle (20S proteasome) COP9 signalosome Dendritic cells Death receptor 4/5 Deubiquitinase Ubiquitin-activating enzyme Ubiquitin-conjugating enzyme Ubiquitin-ligating enzyme Ubiquitin-chain elongation factor Eukaryotic translation initiation factor 2 Endoplasmic reticulum Endoplasmic reticulum-associated degradation Fas-associated protein with death domain
Current Pharmaceutical Design, 2011, Vol. 17, No. 00
FDA HECT
= =
HIF-1 HslV IFN- IPOD IB iPr JAMM JNK JUNQ LMP2 or LMP7 MALT Mcl-1 MDC1
= = = = = = = = = = = = =
MECL1
=
MHC I
=
MJD
=
MYC NEMO NF-B OTU PA(700/28) PML PNPase Poh1 polyUb POMP PUMA
= = = = = = = = = = =
REG RING RP Rpn Rpt TRAIL
= = = = = =
TRIP1 Uba6 Ube1 UCH USP UPS
= = = = = =
9
Food and Drug Administration Homologous to E6-Associated Protein C-Terminus Hypoxia-inducible factor-1 Heat shock locus V Interferon- Insoluble protein deposit Inhibitor B Immunoproteasome JAB1/MPN/Mov34 metalloenzyme c-Jun N-terminal kinase Juxta-nuclear quality control Low mass protein 2 or 7 Mucosa-associated lymphoid tissue Myeloid cell leukemia-1 protein Mediator of DNA damage checkpoint protein 1 Multicatalytic endopeptidase complex subunit 1 Major histocompatibility complex class I Machado-Joseph disease protein domain protease Myelocytomatosis oncogene NF-B essential modulator Nuclear factor-B Ovarian tumor protease Proteasome activator Promyelocytic leukemia Polynucleotide phosphorylase Pad one homolog-1 Polyubiquitin Proteasome maturation protein p53 upregulated modulator of apoptosis Regulator Really interesting new gene (19S proteasome) regulatory particle Regulatory particle non-ATPase-like Regulatory particle ATPase-like Tumor necrosis factor-related apoptosis-inducing ligand Thyroid receptor interactor 1 Ubiquitin-activating enzyme 6 Ubiquitin-activating enzyme 1 Ubiquitin C-terminal hydrolase Ubiquitin-specific protease Ubiquitin-proteasome system
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Received: February 1, 2011
Accepted: April 19, 2011
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