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Zanin, Sofia (2014) Effects of different CK2 inhbition strategies in tumor cells. [Ph.D. thesis]

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Abstract (english)

Protein kinase CK2, constituted by two catalytic (a and/or a’) and two regulatory (b) subunits, is a highly conserved kinase which phosphorylates a huge number of substrates and is involved in different cellular pathways and functions. It has a major anti-apoptotic role, it enhances the apoptosis resistance (MDR) phenotype, and it is abnormally expressed in a wide variety of cancers, where it operates as a “cancer driver” by creating a cellular environment favorable to the development, growth and propagation of malignancy. Since CK2 expression is not linked to a specific type of cancer, its targeting could be a successful strategy, because of its very general applicability and widespread effects. Importantly, tumor cells are more sensitive to CK2 inhibition than normal ones, probably because they rely more on CK2 for their survival, accordingly to the concept of cancer addition to CK2 (Ruzzene and Pinna, 2010). Therefore, CK2 represents a suitable target for developing anticancer drugs.
Different compounds have been developed so far as CK2 inhibitors, useful not only for investigating CK2 physiological functions, but also as possible therapeutic tools. The majority of them act targeting the ATP-binding site of CK2; some compounds have shown high potency and specificity toward the kinase, and have disclosed a proapoptotic effect in cancer cells more evident than in normal ones.
The research presented in this thesis provides examples of different strategies to target protein kinase CK2, in order to selectively reduce its activity in tumor cells and to produce cellular effects which can counteract the malignant transformation. In particular, we used: 1) CX-4945 and CX-5011, ATP-competitive CK2 inhibitors (Pierre et al. 2011); 2) K137-E4, a bi-functional inhibitor designed to compete with both the ATP and the peptide binding sites of CK2; 3) a compound called CRIBI-300, derived from CIGB-300, designed to prevent the phosphorylation of specific CK2 substrates (Perea et al., 2004). The three studies are summarized below. A fourth study is also described, which exploited a compound, TBID, developed from a CK2 inhibitor but modified to become selective toward another protein kinase, HIPK2.

Effects of the ATP-competitive CK2 inhibitors CX-4945 and CX-5011 in apoptosis-resistant cells

CX-4945 and CX-5011 inhibitors (developed by Cylene Pharmaceuticals) act competing with ATP for the binding to the catalytic pocket of the CK2. These compounds are very potent and selective in inhibiting CK2 (Pierre at al., 2011; Battistutta et al., 2012): CX-4945, in particular, has shown good pharmacological features and has advanced in clinical trials with promising outcomes. However, the CX compounds had never been used in apoptosis-resistant cells. In this work we demonstrate that CX-4945 and CX-5011 are efficient in reducing endogenous CK2 activity and in inducing apoptosis in several pairs of apoptosis-sensitive and resistant tumor cell lines. Furthermore, we also observed that resistant cells which express the drug-extruding pump P-gp are sensitized by CX-4945 towards conventional antitumor drugs. In fact, we found that doxorubicin uptake in resistant cells is increased, and that combined treatment with CX-4945 and vinblastine produces synergistic effects on cell death. In summary, our data suggest that CX inhibitors can be considered as a valid therapeutic strategy also in case of pharmacological resistance.
Effects of CK2 bi-functional inhibitors in tumor cells
A very new strategy to target CK2 is based on compounds denoted as bi-functional or bi-substrate inhibitors, designed to hit both the ATP and the substrate sites of the kinase at the same time, in order to improve selectivity toward CK2. Among these compounds, K137-E4 has been recently developed in our laboratory and characterized by in vitro studies; it was found to strongly inhibit recombinant CK2 (IC50=0.025 uM) and to be very selective. In the study presented in this thesis, we had the aim of investigating the employment of this compound in cells. We first demonstrated that it is also able to inhibit the activity of native CK2 towards cellular substrates. However, this was performed by means of in vitro phosphorylation assay, while, when we used K137-E4 for cell treatment we did not observed any effect on CK2 activity and cell viability. We therefore supposed that the compound, quite hydrophilic, is not cell permeable. Studies are under investigation to modify the molecule structure in order to improve its cell permeability, without significantly decreasing its inhibitory capacity. At present, we found that the K137-E4 molecule, in virtue of its impossibility to cross plasma membrane, can be useful to study CK2 ecto-kinase, that portion of this enzyme that resides at the external surface of cells (Kubler et al., 1989). We demonstrated that it is able to inhibit CK2 ecto-kinase, but this has not effect on cell viability of tumor and non-tumor cells. This finding, in conjunction with the observation that CK2 ecto-kinase activity seems to be similar in tumor and not-tumor cells, suggests that CK2 ecto-kinase is not implied in cell survival and tumor-related events.
In vitro and in cell effects of peptides targeting CK2 substrates
A recently introduced approach to target CK2 is based on the development of a cyclic peptide called CIGB-300, which interferes with the phosphorylation site of specific CK2 substrates, rather than inhibiting the enzyme per se (Perea et al., 2004). CIGB-300 is already employed in clinical trials (Perea et al., 2011), however, its mechanism of action is only partially understood. We therefore exploited a new synthetized peptide, denoted as CRIBI-300, with the same functional domain of the parental CIGB-300, and we performed in vitro and in cell studies, comparing it with CIGB-300 and several other derivatives. We found that CK2 activity in vitro is affected by CRIBI-300 peptide, but with different effects accordingly to the type of substrate used: inhibition is observed only towards substrates which are strictly dependent on the presence of CK2 b for their phosphorylation by CK2, while the activity towards substrates which are preferentially phosphorylated by the CK2 monomeric a is rather stimulated by CRIBI-300. This suggests that CRIBI-300 could interfere with the CK2 holoenzyme structure, producing an unstable and/or unfunctional tetrameric conformation which prevents the phosphorylation of b-dependent substrates.
When we performed cell treatment experiments, we also found that CRIBI-300 induces a strong reduction of endocellular CK2 activity, but this is accompanied by an early and rapid loss of CK2 protein amount. In parallel, cell death was also induced by CRIBI-300, but it was not due to apoptosis. Moreover, we observed a loss in the amount of also other proteins beside CK2; alteration in the activity of proteolytic systems occurs as well, with the activation of lysosomal proteases and the blockage of proteasome machinery. All the effects appear more evident in tumor than in non-tumor cells.
We then analyzed the effects of CRIBI-300 derived peptides, with single aminoacid substitutions or large sequence differences. Interestingly, we found that the Tat sequence (the portion of CRIBI-300 introduced to render it cell permeable (Holm et al., 2006)) is essential for its activity towards CK2 in cells, but not sufficient per se, being specific aminoacids in the remaining part of CRIBI-300, crucial for producing effects.
Of the many effects evoked by CRIBI-300, we wondered if and which ones are mediated by its action on CK2. We found that the reduction of CK2 expression (obtained by RNA-interference cellular experiments) also attenuates some of the CRIBI-300 effects, although not all. Moreover, those CRIBI-300 sequence alterations which prevent in vitro effects on CK2 are also able to reduce cellular effects. We therefore concluded that CK2 is indeed an early and important target of CRIBI-300. However, additional mechanisms of action of this compound should exist to explain all the observed effects, and this suggests that extreme caution is required for its employment at a clinical level.

Effects of TBID inhibitor on cellular HIPK2 activity
A collateral study presented in this thesis concerns a compound, TBID, derived from a CK2 inhibitor (TBI) but modified in structure to become selective for a different kinase, HIPK2 (homeodomain-interacting protein kinase 2), a Ser/Thr kinase controlling cell proliferation and survival (D’Orazi et al., 2012), whose investigation has been hampered by the lack of specific inhibitors able to dissect its cellular functions. TBID is an ATP-competitive inhibitor very potent towards HIPK2 in vitro (IC50= 0.33 μM) and very selective. Here we show that it is also cell permeable, being able to inhibit endocellular HIPK2 activity, and to reduce the phosphorylation state of a HIPK2 target, Ser46 of p53 protein. Since TBID is not cytotoxic under the conditions used to check its effects on cellular HIPK2 activity, we propose TBID as the only tool presently available to down regulate cellular HIPK2.

Altogether, the results presented in this thesis demonstrate that kinase inhibition is an extremely versatile tool to be used in cells, exploitable either to investigate on the role of a specific kinase or to block an unwanted hyperactivity. In particular, in the case of CK2 inhibitors, we analyzed different strategies. Although for the moment the more effective and convincing one is still that represented by the classical ATP-site directed compounds, other approaches are also presented, which need further investigation but could be promising in term of improved specificity or more targeted effects.

Abstract (italian)

La proteinchinasi CK2, costituita da due subunità catalitiche (a e/o a ') e due subunità regolatorie (b), è un enzima altamente conservato, che fosforila un gran numero di substrati ed è coinvolto in diverse vie di segnale e funzioni cellulari. CK2 svolge un importante ruolo anti-apoptotico, è coinvolta nel fenomeno della farmacoresistenza all’apoptosi, ed è altamente espressa in un'ampia varietà di tumori, dove opera come un "promotore cancerogeno" creando un ambiente cellulare favorevole alla sviluppo, alla crescita, e alla propagazione della malignità. Poiché la sua sovraespressione non è direttamente connessa ad uno specifico tipo di tumore, colpire CK2 può diventare un’ interessante strategia di successo data la sua generale applicabilità e suoi diffusi effetti. È importante sottolineare che le cellule tumorali sono più sensibili all'inibizione di CK2 rispetto a quelle normali, probabilmente perché sono più dipendenti da CK2 per la loro sopravvivenza, e questo va in accordo con il recente concetto di “cancer addiction” a CK2 (Ruzzene e Pinna, 2010). Pertanto, CK2 rappresenta un obiettivo adatto per lo sviluppo di farmaci antitumorali.
Finora sono stati sviluppati diversi inibitori di CK2, utili non solo per indagare il suo ruolo fisiologico, ma sfruttati anche come possibili strumenti terapeutici. La maggior parte di questi composti agisce bloccando il sito di legame per l’ATP dell’enzima; alcuni di questi hanno dimostrato elevato potere inibitorio e specificità verso la chinasi, e si sono rivelati più efficaci nell’indurre apoptosi in cellule tumorali rispetto a quelle normali.
La ricerca presentata in questa tesi fornisce esempi di diverse strategie di inibizione mirate a bloccare CK2, al fine di ridurre selettivamente la sua attività nelle cellule tumorali e di produrre effetti cellulari che possono contrastare la trasformazione maligna. In particolare, abbiamo utilizzato: 1) CX-4945 e CX-5011, inibitori di CK2 ATP- competitivi (Pierre et al., 2011); 2) K137-E4, un inibitore bifunzionale progettato per competere simultaneamente con ATP e con il sito di legame per il peptide substrato di CK2; 3) CRIBI-300, un composto derivato da CIGB-300, progettato per impedire la fosforilazione di substrati specifici da parte di CK2 (Perea et al., 2004). Questi tre argomenti di ricerca sono riassunti di seguito. Viene presentato anche un quarto studio che ha riguardato un composto, TBID, sviluppato partendo da un inibitore di CK2, modificandolo per renderlo selettivo nei confronti di un'altra proteinchinasi, HIPK2.

Effetti degli inibitori di CK2 ATP-competitivi CX-4945 e CX-5011 in cellule resistenti all’apoptosi
Gli inibitori CX-4945 e CX-5011 (sviluppati dalla Cylene Pharmaceuticals) agiscono competendo con l’ATP per il legame nella tasca catalitica di CK2. Questi composti sono molto potenti e selettivi nell’inibire CK2 (Pierre et al., 2011; Battistutta et al., 2012), il CX-4945 in particolare ha mostrato buone proprietà farmacologiche ed è in sperimentazione clinica nell’uomo con promettenti risultati. Tuttavia, i composti CX non sono mai stati utilizzati in cellule resistenti all’apoptosi. In questo lavoro dimostriamo come CX-4945 e CX-5011 siano efficaci nel ridurre l’attività endogena di CK2 e nell’indurre apoptosi in diverse linee cellulari tumorali sensibili e resistenti all’apoptosi. Abbiamo inoltre trovato che le cellule resistenti che esprimono una pompa di estrusione dei farmaci, la P-gp, vengono rese sensibili a farmaci antitumorali convenzionali grazie all’uso di CX-4945. Infatti abbiamo trovato che l’accumulo di doxorubicina viene incrementato in cellule resistenti e che il trattamento combinato con CX-4945 e vinblastina produce effetti sinergici sulla morte cellulare. Pertanto, i nostri dati suggeriscono che gli inibitori CX possono essere considerati come una valida strategia terapeutica anche nei casi di resistenza farmacologica.
Effetti di inibitori di CK2 bifunzionali in cellule tumorali
Una nuova strategia per inibire CK2 è basata su composti definiti come inibitori bifunzionali o bisubstrato, disegnati per legarsi contemporaneamente ai siti di legame per l’ATP e per il substrato di CK2, con lo scopo di aumentarne la selettività per CK2. Tra questi composti il K137-E4 è stato recentemente sviluppato e caratterizzato in vitro nel nostro laboratorio: è stato dimostrato che è molto potente nell’inibire la CK2 ricombinante (IC50 = 0,025 uM) e che ha buona selettività. Nello studio presentato in questa tesi, ci siamo proposti di analizzare la possibilità di utilizzo di questo composto anche in cellule. Innanzitutto abbiamo dimostrato che il K137-E4 è in grado di inibire l’attività di CK2 nativa nei confronti di substrati cellulari. Tuttavia, questo si riferisce ad esperimenti in vitro, mentre quando abbiamo trattato le cellule con il K137-E4 non abbiamo osservato alcun effetto né sull’attività di CK2 né sulla vitalità cellulare. Abbiamo pertanto ipotizzato che il composto, essendo piuttosto idrofilico, non fosse in grado di attraversare la membrana cellulare. Sono tuttora in corso modifiche strutturali della molecola mirate ad aumentarne la permeabilità cellulare senza diminuirne significativamente la sua capacità inibitoria. Ad oggi, abbiamo pensato che il K137-E4, in virtù della sua impossibilità di attraversare la membrana plasmatica, può essere utile per studiare l’attività ectochinasica di CK2, cioè di quella porzione di enzima che risiede sulla superficie esterna delle cellule (Kubler et al., 1989). Abbiamo infatti dimostrato che questo composto è capace di inibire CK2 ectochinasica, ma che ciò non ha alcun effetto sulla vitalità cellulare né di cellule tumorali né di cellule non tumorali. Questa scoperta, assieme all’osservazione che l’attività ectochinasica di CK2 sembra essere simile in cellule tumorali e non, suggerisce che la CK2 ectochinasica non è implicata nella sopravvivenza cellulare e negli eventi correlati alla tumorigenesi.
Effetti in vitro e in cellule di peptidi mirati a legare substrati di CK2
Un nuovo approccio recentemente introdotto per colpire CK2 è basato sullo sviluppo di un peptide ciclico, chiamato CIGB-300, che interferisce con la fosforilazione di specifici substrati di CK2 piuttosto che inibire con l’enzima per se (Perea et al., 2004). CIGB-300 è già impiegato in studi clinici (Perea et al., 2011), tuttavia il suo meccanismo d’azione è solo parzialmente conosciuto. Abbiamo dunque sfruttato un nuovo peptide sintetico, chiamato CRIBI-300, con lo stesso dominio funzionale del CIGB-300, e abbiamo effettuato studi in vitro ed in cellule, comparandolo con il CIGB-300 e altri suoi derivati. Abbiamo scoperto che l’attività di CK2 in vitro può essere influenzata dal peptide CRIBI-300, ma con effetti differenti a seconda del tipo di substrato utilizzato: abbiamo osservato inibizione solo per quei substrati la cui fosforilazione da parte di CK2 è strettamente dipendente dalla presenza della subunità regolatoria b, mentre troviamo stimolazione da parte del CRIBI-300 nei confronti di substrati che sono fosforilati preferenzialmente dalla subunità catalitica a. Questi dati suggeriscono che il CRIBI-300 potrebbe interferire con la struttura dell’oloenzima CK2, dando luogo ad una conformazione tetramerica instabile e non funzionale e impedendo la fosforilazione di substrati b-dipendenti.
Anche in esperimenti di trattamento cellulare, abbiamo trovato che CRIBI-300 induce una forte riduzione dell’attività cellulare di CK2, che è però accompagnata da una precoce e rapida perdita della quantità proteica di CK2. In parallelo, CRIBI-300 induce anche morte cellulare, ma non per apoptosi. Inoltre, abbiamo osservato diminuzione delle quantità di altre proteine, oltre a CK2, e un’alterazione dell’attività dei sistemi proteolitici con l’attivazione di proteasi lisosomiali e il blocco del proteasoma. Tutti questi effetti appaiono più evidenti in cellule tumorali che in cellule non tumorali.
Abbiamo poi analizzato gli effetti di derivati peptidici del CRIBI-300, con sostituzioni di singoli aminoacidi o con sequenze diverse. E’ interessante il fatto che abbiamo trovato che la sequenza Tat (la porzione del CRIBI-300 introdotta per renderlo permeabile alla cellula (Holm et al., 2006)) è essenziale per la sua attività su CK2 in vitro e in cellula, ma non è sufficiente di per se dal momento che specifici amminoacidi nella parte funzionale del CRIBI-300 (la sequenza non corrispondente a Tat) risulta essere cruciale per produrre gli effetti. Dei molti effetti causati dal CRIBI-300, abbiamo cercato di capire quali fossero mediati dalla sua azione su CK2. Abbiamo trovato che la riduzione dell’espressione di CK2 (ottenuta mediante esperimenti di “RNA interference”) attenua alcuni degli effetti del CRIBI-300, sebbene non tutti. Inoltre, quelle modifiche della sequenza del CRIBI-300 che impediscono i suoi effetti in vitro su CK2 sono anche capaci di ridurne gli effetti a livello cellulare. Possiamo perciò concludere che CK2 è sicuramente uno dei più importanti bersagli di CRIBI-300. Tuttavia altri meccanismi d’azione di questo composto devono esistere per spiegarne tutti gli effetti osservati, e ciò suggerisce quindi che un’estrema cautela è richiesta per l’utilizzo di questo composto.
Effetti dell’inibitore TBID sull’attivita’ cellulare di HIPK2
Uno studio collaterale presentato in questa tesi riguarda il composto TBID, che deriva da un inibitore di CK2, il TBI, ma che è stato modificato nella struttura per renderlo selettivo nei confronti di un’altra chinasi, HIPK2 (Homeodomain-interacting protein kinase 2), una Ser/Thr chinasi che controlla la proliferazione e sopravvivenza cellulare (D’Orazi et al., 2012) il cui studio è stato rallentato dalla mancanza di inibitori specifici capaci di svelarne le funzioni cellulari. TBID è un inibitore ATP-competitivo molto potente nei confronti di HIPK2 in vitro (IC50 = 0,33 uM) e molto selettivo. In questa tesi mostriamo che TBID è anche in grado di entrare nelle cellule, dimostrando che inibisce l’attività di HIPK2 intracellulare e riduce la fosforilazione della Ser46 di p53, un sito fosforilato da HIPK2. Dal momento che TBID non è citotossico nelle condizioni utilizzate per analizzarne gli effetti sull’attività di HIPK2 cellulare, proponiamo TBID come l’unico strumento attualmente disponibile per inibire HIPK2 in cellule.
I risultati presentati in questa tesi dimostrano che l’inibizione di chinasi rappresenta uno strumento estremamente versatile per l’utilizzo nelle cellule, sia per analizzare il ruolo di una specifica chinasi, sia per bloccarne una non desiderata iperattività. In particolare, nel caso di inibitori di CK2 abbiamo analizzato diverse strategie. Sebbene al momento la più efficace e convincente rimanga quella rappresentata dai classici composti ATP-competitivi, abbiamo presentato altri approcci che, pur necessitando di ulteriori studi, potranno in futuro dimostrarsi promettenti in termini di aumentata specificità o di maggiore selettività degli effetti prodotti.

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EPrint type:Ph.D. thesis
Tutor:Ruzzene, Maria
Data di deposito della tesi:31 January 2014
Anno di Pubblicazione:31 January 2014
Key Words:Fosforilazione proteica/ Protein phosphorylation Protein chinasi CK2/Protein kinase CK2 Inibitori di CK2/CK2 inhibitors Protein chinasi HIPK2/Protein kinasi HIPK2
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:6376
Depositato il:31 Oct 2014 13:30
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