R E V I E W A R T I C L E
a-enolase: a promising therapeutic and diagnostic tumor target Michela Capello, Sammy Ferri-Borgogno, Paola Cappello and Francesco Novelli
Department of Medicine and Experimental Oncology, Center for Experimental Research and Medical Studies (CeRMS), San Giovanni Battista Hospital, University of Turin, Italy
Keywords a-enolase; cancer; immune response; post-translational modifications; tumor-associated antigen
Correspondence F. Novelli, Center for Experimental Research and Medical Studies (CeRMS), San Giovanni Battista Hospital, Via Cherasco 15, 10126 Turin, Italy Fax: +39 011 633 6887 Tel: +39 011 633 4463 E-mail: franco.novelli@unito.it
(Received 5 November 2010, revised 19 January 2011, accepted 21 January 2011)
a-enolase (ENOA) is a metabolic enzyme involved in the synthesis of pyru- vate. It also acts as a plasminogen receptor and thus mediates activation of plasmin and extracellular matrix degradation. In tumor cells, EMOA is it is upregulated and supports anaerobic proliferation (Warburg effect), expressed at the cell surface, where it promotes cancer invasion, and is sub- jected to a specific array of post-translational modifications, namely acety- lation, methylation and phosphorylation. Both ENOA overexpression and its post-translational modifications could be of diagnostic and prognostic value in cancer. This review will discuss recent information on the biochemical, proteomics and immunological characterization of ENOA, particularly its ability to trigger a specific humoral and cellular immune response. In our opinion, this information can pave the way for effective new therapeutic and diagnostic strategies to counteract the growth of the most aggressive human disease.
doi:10.1111/j.1742-4658.2011.08025.x
Introduction
tissues [1,7–9]. The monomer of ENOA consists of a smaller N-terminal domain (residues 1–133) and a lar- ger C-terminal domain (residues 141–431). In eukarya, enzymatically active enolase consists of a dimeric form in which two subunits face each other in an antiparal- lel manner [1,10]; some eubacterial enolases, by con- trast, are octameric [11]. Enolase can form homo- or heterodimers, such as aa, ab, bb, ac and cc [1].
and b-enolase,
Enolase is a metalloenzyme that catalyzes the dehydra- tion of 2-phospho-d-glycerate to phosphoenolpyruvate in the second half of the glycolytic pathway. In the reverse reaction (anabolic pathway), which occurs dur- ing gluconeogenesis, the enzyme catalyzes the hydra- tion of phosphoenolpyruvate to 2-phospho-d-glycerate [1,2]. Enolase is found from archaebacteria to mam- mals, and its sequence is highly conserved [3]. In mam- mals, three genes, ENO1, ENO2 and ENO3 encode for the enzyme, a-enolase (ENOA), three isoforms of c-enolase respectively, with high sequence identity [4–6]. The expression of these iso- forms is tissue specific: ENOA is present in almost all adult tissues, b-enolase is expressed in muscle tissues and c-enolase is found in neurons and neuroendocrine
Apart from its enzymatic activity, in many prokary- otic and eukaryotic cells, ENOA is expressed on the cell surface, where it acts as a plasminogen receptor promoting cell migration and cancer metastasis [12– 23]. Moreover, ENO1 can be translated into a 37 kDa protein, c-myc promoter-binding protein (MBP-1), by using an alternative start codon [24]. MBP-1 lacks the
Abbreviations EGFR, epidermal growth factor receptor; ENOA, a-enolase; ERK, extracellular signal-regulated kinase; MBP-1, c-myc promoter-binding protein; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; PAI-1, plasminogen activator inhibitor-1; PTM, post- translational modification; TAA, tumor-associated antigen; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator; uPAR, urokinase-type plasminogen activator receptor.
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first 96 residues of ENOA and localizes in the nucleus, where it binds to the c-myc P2 promoter and acts as a transcription repressor, leading to tumor suppression [25–27]. ENOA associates with MBP-1 in the tran- scriptional regulation of the oncogene c-myc [28].
ENOA is a surface plasminogen-binding receptor in tumors
receptor
signal-regulated kinase
In breast, lung and pancreatic neoplasia, ENOA is localized on the surface of cancer cells [29–31], whereas in melanoma and nonsmall cell lung carcinoma cells it can also be secreted by exosomes [32,33]. How ENOA is displayed on the cell surface remains unknown. Many glycolytic enzymes and cytosolic proteins that lack N-terminal signal peptide reach the surface of eukaryotic cells [34]. In mammal cells, some export routes of unconventional protein secretion have been postulated: membrane blebbing, membrane flip-flop, endosomal recycling or a plasma membrane trans- porter [35]. One possibility is that phosphoinositides recruit ENOA and translocate it to the cell surface [36]. It is not known if surface ENOA is also present as a monomer. As the monomeric form is catalytically inefficient it could be available to interact with other proteins that mediate its transport to the cell surface [37]. However, in breast cancer cells, surface ENOA maintains its catalytic activity, suggesting that cell sur- face localization does not affect this function [31].
its inhibitor a2-antiplasmin and enhancement of the proteolytic activity of cell-bound plasmin [13,51]. Pro- teolysis mediated by cell-associated plasmin contributes to both physiological processes, such as tissue remodel- ing and embryogenesis, and to pathophysiological processes, such as cell invasion, metastasis and inflam- matory response [19,45]. A noteworthy positive corre- lation exists between elevated levels of plasminogen activation and malignancy [46,52]. Higher expression levels of uPA and ⁄ or plasminogen activator inhibitor-1 (PAI-1) in tumor tissues correlate with aggressiveness and poor prognosis. ENOA takes part, together with (uPAR), urokinase plasminogen activator integrins and some cytoskeletal proteins, in a multipro- tein complex, called metastasome, responsible for adhesion, migration and proliferation in ovarian can- cer cells [53]. In human follicular thyroid carcinoma cells, retinoic acid causes a decrease in ENOA levels that coincides with their reduced motility [54], and cell surface ENOA is enhanced in breast cancer cells ren- dered superinvasive following paclitaxel treatment [55]. In pancreatic cancer patients, deregulated expression of many proteins involved in the plasminogen pro-fibri- nolytic cascade (annexin A2, PAI-2, uPA, uPAR, MMP- 1 and MMP-10) correlates with survival [56–59]. In the same tumor, tPA activates a mitogenic signal mediated by extracellular (ERK)-1 ⁄ 2 through epidermal growth factor receptor (EGFR) and annexin A2 [60,61]. These proteins probably form a complex that also includes ENOA, as it has been pulled down with annexin A2, cytokeratin 8 and tPA in raft membrane fractions of pancreatic cancer cells [62].
ENOA is a tumor-associated antigen (TAA)
Interaction of
Cell surface ENOA is one of the many plasminogen- binding molecules that include actin [38], gp330 [39], cytokeratin 8 [40], histidine-proline rich glycoprotein [41], glyceraldehyde-3-phosphate dehydrogenase [42], annexin II [43], histone H2B [44] and gangliosides [14]. ENOA and most of these proteins have C-terminal lysines predominantly responsible for plasminogen acti- vation [45]. the plasminogen lysine- binding sites with ENOA is dependent upon recognition of ENOA C-terminal lysines K420, K422 and K434 [14]. In view of the surface potential of the human ENOA crystal structure, an additional plasminogen binding site that includes K256 has been proposed [10].
TAAs are self-proteins that can trigger multiple spe- cific immune responses in the autologous host [63]. Activation of the immune system against TAAs occurs at an early stage of tumorigenesis, as illustrated by the detection of high titers of autoantibodies in patients with early-stage cancer [64], and correlates with the progression of malignant transformation [65]. It is not entirely clear how TAAs are able to trigger humoral responses, especially as many of those discovered so far are intracellular proteins, but are thought to be altered in a way that renders the proteins immunogenic [66,67]. Several hypotheses have been proposed: these self-proteins could be overexpressed, mutated, misfold- ed, aberrantly degraded or localized so that autoreac- tive immune responses in cancer patients are induced [65,68,69]. Moreover TAAs that have undergone post- translational modifications (PTMs) (e.g. glycosylation,
Binding with ENOA lysyl residues leads to activa- tion of plasminogen to plasmin by the proteolytic action of either tissue-type (tPA) or urokinase-type (uPA) plasminogen activators [19,46]. Plasmin is a ser- ine protease with a broad spectrum substrate, includ- ing fibrin, extracellular matrix components (laminin, fibronectin) and proteins involved in extracellular matrix degradation (matrix metalloproteinases, such as MMP3) [47–50]. Binding of plasminogen to the cell surface has profibrinolytic consequences: enhancement of plasminogen activation, protection of plasmin from
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phosphorylation, acetylation, oxidation and proteolytic cleavage) may be perceived as foreign by the immune system [66–68]. The immune response against such immunogenic epitopes of TAAs induces the production of autoantibodies as serological biomarkers for cancers [70]. Both its overexpression in tumors and its ability to induce a humoral and ⁄ or cellular immune response in cancer patients classify ENOA as a true TAA.
Results from a bioinformatic study support a correla- tion between ENOA expression and tumorigenicity [52,77]. Moreover, ENOA’s enzymatic activity may also be increased in breast tumor tissue, especially in metastatic sites [82,83]. Increased ENOA expression can influence chemotherapy treatments, as shown in estrogen receptor-positive breast tumors, where it induces tamoxifen resistance [78], and in colorectal car- cinoma cells, where it is overexpressed after 5-fluoro- uracil administration [87].
ENOA expression is increased in tumors
ENOA PTMs in tumors
lines (Table 2)
PTMs are common mechanisms that control signal transduction, protein-protein interaction and transloca- tion [105,106]. Reversed-phase liquid chromatography, nanospray tandem mass spectrometry has been used to characterize ENOA PTMs in several cancer and normal cell (http://www.uniprot.org/ uniprot/P06733) [107–115].
The overexpression of ENOA is associated with tumor development through a process known as aerobic gly- colysis or the Warburg effect [71]. Warburg observed that cancer cells consume more glucose than normal cells and generate ATP by converting pyruvate to lac- tic acid, even in the presence of a normal oxygen sup- ply [72]. The mechanism of the Warburg effect was uncertain until the recent identification of upregulation of glycolytic enzymes by hypoxia-inducible factor. When a solid tumor exceeds 1 mm3, its cells face hyp- oxic stress due to slow angiogenesis [73,74]. Because the ENO1 promoter contains a hypoxia responsive ele- ment [75,76], ENOA is upregulated at the mRNA and ⁄ or protein level in several tumors, including brain [77], breast [78–83], cervix [77,84,85], colon [77,86,87], eye [77], gastric [77,88,89], head and neck [90,91], kid- ney [77], leukemia [92], liver [77,93,94], lung [77,95–99], muscle [77], ovary [77,100], pancreas [29,77,101,102], prostate [77,103], skin [104] and testis [77] (Table 1).
Acetylation, methylation and phosphorylation are the main PTMs (Table 2). Acetylation was found in cervix and colon cancer, leukemia, normal pancreatic ducts and tumoral pancreatic cells. Fourteen acetylated lysine residues are common to leukemia, pancreatic cancer and normal pancreas, and one of them is the only acetylated residue in cervix tumor. Three acetyla- tions are common to both leukemia and pancreatic cancer, whereas three are specific for normal and tumoral pancreatic cells. However, six specific acety- lated lysines were found in pancreatic cancer cells, and
Table 1. Expression of ENOA, the immune response to it and clinical correlations in cancer.
Cancer
ENOA enhanced expression
Immune response to ENOA
Clinical correlations
Ab [69,125]
DP, DFI, M [69,78]
Ab (79%) [91,123,124], T [131,132]
OS, PFS [91]
Ab (33–86%) [120,121]
Ab (7–80%) [30,69,96,99,126–129]
M [93,94] DP, OS, PFS [69,99]
Ab (62%) [119], T [29]
OS, PFS [119]
Ab (38–100%) [104,122]
Brain Breast Cervix Colon Eye Gastric Head and neck Kidney Leukemia Liver Lung Muscle Ovary Pancreas Prostate Skin Testis
m [77] m (68%), p, e (100%) [78–83] m, p [77,84,85] m, p [77,86,87] m [77] m (73%), p [77,88,89] m (68%), p [90,91] m [77] p (> 50%) [92] m, p (17–80%) [77,93,94] m, p (79–100%) [77,95–99] m [77] m, p [77,100] m (100%), p (82–90%) [29,77,101,102] m, p (100%) [77,103] m [104] m [77]
Percentages indicate the reported frequencies of enhanced ENOA mRNA, protein and enzymatic activity or the frequencies of anti-ENOA Ig. m, mRNA; p, protein; e, enzymatic activity; Ab, antibody production; T, T cell response; DP, disease progression; DFI, disease-free interval; M, malignancy; OS, overall survival; PFS, progression-free survival.
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three in leukemia. The only acetylated serine identified is specific for colon cancer (Table 2).
In pancreatic
Methylation has been assessed in normal and tumor- al pancreas only. Twenty-four aspartate and glutamate residues were found in both cell types. However, five aspartates and five glutamates are specifically methy- lated only in pancreatic cancer (Table 2).
In many cancer patients, including pancreatic [119], leukemia [120,121], melanoma [104,122], head and neck [91,123,124], breast [69,125] and lung [30,69,96,99, 126–129], ENOA has been shown to induce autoanti- cancer body production (Table 1). patients, autoantibodies to ENOA are directed against two upregulated isoforms phosphorylated in Ser 419 [115,119] (Table 2). Protein phosphorylation increases the affinity of peptides for MHC molecules that can be recognized by T cells [130].
Phosphorylation is the PTM that displays the most specific pattern in each cell line. Two serine and one threonine residues were specifically found in cervix cancer, one threonine and one serine in embryonic kid- ney, three serines and two threonines in leukemia; whereas two tyrosine residues were found in both leu- kemia and lung cancer and one serine in both tumoral and normal pancreas.
In pancreatic cancer, ENOA elicits a CD4+ and CD8+ T cell response both in vitro and in vivo [29]. Anti-MHC class I Ig inhibited the cytotoxic activity of ENOA-stimulated CD8+ T cell against pancreatic tumor cells, but no MHC class I restricted peptide of ENOA has been identified so far. Moreover, in pancre- atic ductal adenocarcinoma patients, production of anti-ENOA IgG is correlated with the ability of T cells to be activated in response to the protein [29], thus confirming the induction of a T and B cell integrated antitumor activation against ENOA. In oral squamous cell carcinoma, an HLA-DR8-restricted peptide (amino acid residues 321–336) of human ENOA recognized by CD4+ T cell and able to confer cytotoxic susceptibility has been identified [131,132].
Clinical correlations
ENOA in tumor cells is subjected to more acetyla- tion, methylation and phoshorylation than in normal tissues, indicating that many PTMs are associated with cancer development and some are specific for each kind of tissue or cancer. This can reflect the specific activation of pro-mitogenic signaling pathways in tumor cells. In many cases, PTMs regulate the stability and functions of proteins; for example, in metabolic enzymes, acetylation acts as an on ⁄ off switch mecha- nism [116], whereas methylation on carboxylate side- chains enhances hydrophobicity by increasing the affin- ity of proteins for phospholipids [115]. We speculate that PTMs are important mechanisms in the regulation of ENOA functions, localization and immunogenicity.
ENOA induces a specific immune response in tumors
The diagnostic and prognostic value of ENOA expres- sion and production of autoantibodies to it has been illustrated in several tumors (Table 1). In breast can- cer, enhanced ENOA expression is correlated with greater tumor size, poor nodal status and a shorter dis- ease-free interval [78]. In head and neck and nonsmall cell lung cancer, patients with high ENOA expression had significantly poorer clinical outcomes than low expressers, including shorter overall- and progression- free survival [91,99]. In hepatocellular cancer, expres- sion of ENOA increased with tumor de-differentiation and correlated positively with venous invasion [93,94].
phosphorylated ENOA autoantibodies
Several TAAs induce the production of IgG autoanti- body in cancer patients via an integrated immune response triggered by CD4+ T cells, CD8+ T cells and B cells. TAAs released by secretion, shedding or tumor cell lysis are captured by antigen presenting cells, processed and presented by either major histocompatibility complex (MHC) class I or MHC class II molecules for priming and activation of CD8+ and CD4+ T cells, respectively. Uptake of antigen by B cells also occurs and is driven by membrane Ig, leading to MHC class II antigen presentation to CD4+ T cells. Activated CD4 + T cells, through the secretion of appropriate cytokines, trigger B cells to produce IgG against the same TAA [117], and CD8+ T cells to differentiate into TAA-spe- cific cytotoxic T lymphocytes. In vivo maintenance and survival of TAA-specific cytotoxic T lymphocytes is also dependent on cytokines released by CD4 + T cells [118]. This coordinated immune response suggests that IgGs against TAA are not only a diagnostic tool, but also allow the selection of TAAs for cancer immunotherapy.
In breast and lung cancer patients, anti-ENOA autoantibodies are decreased in the advanced stages of the disease [69]. In pancreatic cancer, detection of au- toantibodies against Ser 419 phosphorylated ENOA usefully complemented the diagnostic performance of serum CA19.9 levels up to 95%. The presence of this humoral response was also correlated with a longer progression-free survival upon gemcitabine treatment and overall survival, supporting the clinical significance of [119]. The concept that autoantibody levels can also function as markers for the diagnosis and prognosis of cancers has been extensively pursued [69,133].
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pancreas-specific Ser 419 phosphorylated ENOA is upregulated and induces the production of autoanti- bodies with diagnostic and prognostic value (Fig. 1).
Pancreatic ductal cell
Acknowledgements
Pancreatic cancer cell
Non-pancreatic cancer cell
The authors thank Dr W. Zhou for discussion on the role of post-translational modifications in the regulation of protein functions and Dr J. Iliffe who critically reviewed the manuscript. This work was supported in part by grants from the Associazione Italiana Ricerca sul Cancro (AIRC); Fondazione San Paolo (Special Project Oncology); Ministero della Salute: Progetto strategico, ISS-ACC, Progetto integrato Oncologia; Regione Piemonte: Ricerca Industriale e Sviluppo Precompetitivo (BIOPRO and ONCOPROT), Ricerca (BIOTHER), Industriale ‘Converging Technologies’ Progetti strategici su tematiche di interesse regionale o sovra regionale (IMMONC), Ricerca Sanitaria Finalizzata, Ricerca Sanitaria Applicata; Ribovax Biotechnologies (Geneva, Switzerland) and Fondazione Italiana Ricerca sul Cancro (FIRC).
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