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Salizzato, Valentina (2014) Protein kinase CK2: a new target to overcome imatinib-resistance in chronic myeloid leukemia cells. [Tesi di dottorato]

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Abstract (inglese)

Chronic myeloid leukemia (CML), a malignant myeloproliferative disorder of hematopoietic system, is driven by the chromosomal translocation [t(9;22)(q34;q11)], yielding the Philadelphia chromosome and generating a fusion gene that encodes the Bcr-Abl protein, a constitutively active tyrosine kinase necessary and sufficient for the initiation, maintenance and progression of CML [Faderl S. et al., 1999]. Despite the great efficacy of the Bcr-Abl-specific inhibitor imatinib, which represents the gold-standard drug of choice for CML patients, resistance to this drug is recognized as a major problem in CML therapy failure [Bixby D. and Talpaz M., 2009]. In this context, this work focuses on the analysis of the protein kinase CK2, a ubiquitous, pleiotropic and constitutively active Ser/Thr kinase, composed of two catalytic (alpha and/or alpha prime) and two regulatory (beta) subunits. CK2 is abnormally elevated in a wide variety of tumors, where it does not induce directly the cancer but it is critically required to create a cellular environment favourable to the development of neoplasia, mainly through its anti-apoptotic and pro-survival role [Ruzzene M. and Pinna L.A., 2010].
The goal of the research is to shed light on the role of the protein kinase CK2 in chronic myeloid leukemia oncogenic signaling, using two different CML cell lines, LAMA84 and KCL22, either sensitive (S) or resistant (R) to imatinib.
In my laboratory it had been previously observed that resistant-LAMA84 CML cells, which are characterized by BCR-ABL1 gene amplification [Le Coutre P. et al., 2000], contain a two-fold higher amount of CK2 alpha and CK2 beta, but not CK2 alpha prime, subunits as compared to parental cells [Borgo C. et al., 2013]. Consistently, the quantification of the CK2 subunits demonstrates that CK2 protein is expressed at very high levels compared to total cellular proteins in LAMA84 cells. Subcellular fractionation analysis shows that most CK2 is located in the cytoplasmic fraction of R-LAMA84 cells, where it co-localizes with Bcr-Abl. CK2 and Bcr-Abl are members of the same multi-protein complex(es) only in R-LAMA84 cells, as demonstrated by their co-sedimentation in glycerol-gradients and co-immunoprecipitation. Interestingly, while cell treatment with imatinib does not affect the binding occurring between CK2 and Bcr-Abl, the CK2-specific inhibitor CX-4945 almost abrogates this interaction, suggesting that CK2 kinase activity plays a specific role in the binding.
In spite of the CK2 up-regulation occurring in imatinib-resistant LAMA84 cells, we also demonstrate that imatinib-resistant KCL22 cells express similar protein-level and activity of both CK2 and Bcr-Abl as compared to the sensitive counterpart. Moreover, CK2 co-immunoprecipitates with Bcr-Abl in both KCL22 cell variants. To assess whether CK2 might be a player in imatinib-resistant KCL22 cells, we investigated the complex Bcr-Abl oncogenic network dedicating particular attention to MAPK and PI3K/Akt/mTOR pathways, which have been frequently demonstrated to be up-regulated in cancer cells [Saini K.S. et al., 2013]. We found that resistant KCL22 cells are characterized by a strikingly higher phosphorylation extent of ERK1/2 T202/Y204, as previously reported by Colavita I. et al. (2010), Akt S473 and ribosomal protein S6 (rpS6) S240/4-235/6 as compared to sensitive cells. In R-KCL22 cells, the treatment with high concentrations of imatinib causes a substantial inhibition of ERK1/2 and Akt S473 phosphorylation, while, unexpectedly, it only partially affects the phosphorylation of rpS6, the common downstream effector of MAPK and PI3K/Akt/mTOR pathways. Interestingly, rpS6 phosphorylation is almost abrogated by CK2 down-regulation, as judged by cell treatment with CX-4945, which does not affect ERK1/2 and Akt activities, and by CK2 knocking down by siRNA. Consistent with the down-regulation of rpS6, protein involved in translation initiation, the treatment of R-KCL22 cells with CX-4945 reduces the protein synthesis efficacy of about 50% as compared to the control.
To further assess the contribution of CK2 to chronic myeloid leukemia, the effect of CK2-inhibition on cell viability was examined. CX-4945 significantly reduces the cell viability and induces apoptosis in both LAMA84 and KCL22 cell lines, either sensitive or resistant to imatinib. However, CX-4945 concentrations required to induce apoptosis in imatinib-resistant cells are lower than those effective in sensitive cells, suggesting that resistant cells become more dependent on CK2 for their survival. Interestingly, CX-4945 added in combination with imatinib promotes a synergistic reduction of cell viability in imatinib-resistant CML cell variant, partially rescuing the response to imatinib. In resistant KCL22 cells, we also show that CK2-inhibition sensitizes leukemic cells to the anticancer compounds U0126, an inhibitor of MAPK pathway, and rapamycin, the specific inhibitor of mTORC1 complex. Interestingly, the ternary association of CX-4945 with imatinib and U0126 represents the best effective combination of drugs to reduce the viability of R-KCL22 cells.
Taken together, our results identify CK2 as a pivotal player in CML imatinib-resistance and suggest that CK2 inhibitors might represent promising drugs for combined strategies to overcome CML imatinib-resistance.

Abstract (italiano)

La leucemia mieloide cronica (LMC), una malattia mieloproliferativa maligna del sistema ematopoietico, è determinata dalla traslocazione cromosomica [t(9; 22)(q34, q11)], che causa la formazione del cromosoma Philadelphia e del gene di fusione BCR-ABL1. Tale gene codifica per la proteina Bcr-Abl, una tirosin chinasi costitutivamente attiva, necessaria e sufficiente per l’insorgere, il mantenimento e la progressione della patologia [Faderl S. et al., 1999]. Nonostante la grande efficacia dell’imatinib, inibitore specifico di Bcr-Abl, che rappresenta il farmaco d’elezione per il trattamento dei pazienti affetti da LMC, la resistenza a questo farmaco è riconosciuta come uno dei maggiori problemi del fallimento chemioterapico [Bixby D. and Talpaz M., 2009]. In questo contesto, il lavoro della mia tesi è stato rivolto allo studio della protein chinasi CK2, una serin/treonin chinasi ubiquitaria, pleiotropica e costitutivamente attiva, composta da due subunità catalitiche (alfa e/o alfa prima) e due regolatorie (beta). Il livello proteico di CK2 è anormalmente elevato in un ampio numero di tumori, in cui tuttavia la chinasi non è mai riconosciuta come la causa che scatena la patologia ma risulta essere criticamente necessaria per l’instaurarsi di un ambiente cellulare favorevole allo sviluppo della neoplasia, principalmente grazie al suo ruolo anti-apoptotico e pro-sopravvivenza [Ruzzene M. and Pinna L.A., 2010].
L’obiettivo della ricerca è quello di far luce sul ruolo svolto dalla protein chinasi CK2 nelle vie oncogeniche di segnale che caratterizzano la LMC, utilizzando le due linee cellulari LAMA84 e KCL22, sia sensibili (S) che resistenti (R) all’imatinib.
Nel mio laboratorio era stato precedentemente osservato che le cellule LAMA84 resistenti all’imatinib, caratterizzate dell’amplificazione del gene BCR-ABL1 [Le Coutre P. et al., 2000], contengono una quantità proteica delle subunità CK2 alfa e CK2 beta, ma non CK2 alfa prima, circa due volte superiore rispetto alle cellule sensibili all’imatinib [Borgo C. et al., 2013]. In accordo con questo risultato, la quantificazione proteica delle subunità di CK2 dimostra che il livello della chinasi è marcatamente elevato nelle cellule LAMA84 rispetto alle proteine totali. L’analisi del frazionamento subcellulare mostra che la maggior parte di CK2 si trova nella frazione citoplasmatica delle cellule R-LAMA84, dove co-localizza con Bcr-Abl. CK2 e Bcr-Abl sono membri dello stesso complesso multi-proteico ed interagiscono tra loro solo nelle cellule LAMA84 resistenti all’imatinib, come dimostrato dagli esperimenti di co-sedimentazione in gradienti di glicerolo e di co-immunoprecipitazione. È interessante notare che, mentre il trattamento cellulare con imatinib non influenza l’interazione tra CK2 e Bcr-Abl, il CX-4945, uno specifico inibitore di CK2, abolisce quasi interamente questo legame, suggerendo che l’attività chinasica di CK2 svolga un ruolo specifico nel legame tra le due proteine.
Diversamente da quanto descritto nelle cellule LAMA84, le cellule KCL22 resistenti all’imatinib esprimono un livello proteico, ed un’attività chinasica, sia di CK2 che di Bcr-Abl, simile in cellule sensibili e resistenti all’imatinib. CK2 risulta inoltre interagire con Bcr-Abl in entrambe le varianti cellulari di KCL22. Per valutare se CK2 potesse avere un ruolo nella resistenza all’imatinib anche nelle cellule KCL22, abbiamo studiato la complessa rete oncogenica regolata da Bcr-Abl, dedicando particolare attenzione alle seguenti due vie di trasduzione del segnale: MAPK e PI3K/Akt/mTOR, spesso iperattivate nelle cellule tumorali [Saini K.S. et al., 2013]. E’ stato trovato che, rispetto alle cellule sensibili, le cellule KCL22 resistenti all’imatinib sono caratterizzate da un più elevato grado di fosforilazione delle seguenti proteine nei loro siti regolatori: ERK1/2 (T202/Y204), come precedentemente riportato da Colavita I. et al. (2010), Akt (S473) e rpS6 (S240/4-235/6). Nelle cellule R-KCL22, il trattamento con alte concentrazioni di imatinib riesce ad inibire drasticamente la fosforilazione di ERK1/2 (T202/Y204) e Akt S473, mentre, inaspettatamente, diminuisce solo in parte la fosforilazione di rpS6, l’effettore comune a valle delle vie di segnale MAPK e PI3K/Akt/mTOR. È interessante notare che la fosforilazione di rpS6 è invece praticamente abolita dall’inibizione dell’attività catalitica di CK2. Tale risultato è dimostrato sia dal trattamento cellulare con CX-4945, il quale non altera nè il grado di fosforilazione di ERK1/2 né quello di Akt S473, che dal silenziamento genico tramite interferenza dell’mRNA di CK2. In parallelo al diminuito grado di fosforilazione di rpS6, proteina coinvolta nella fase dell’inizio della traduzione, il trattamento delle cellule R-KCL22 con CX-4945 riduce l’efficacia della sintesi proteica cellulare di circa il 50% rispetto al controllo.
Per valutare ulteriormente il contributo di CK2 nella leucemia mieloide cronica, è stato esaminato l’effetto dell’inibizione dell’attività chinasica di CK2 sulla vitalità cellulare. Il trattamento cellulare con CX-4945 riduce in modo significativo la vitalità delle cellule e induce apoptosi in entrambe le linee cellulari LAMA84 e KCL22, sia nella variante sensibile che in quella resistente all’imatinib. Tuttavia, le concentrazioni di CX-4945 necessarie per indurre apoptosi nelle cellule resistenti sono inferiori rispetto a quelle efficaci nelle cellule sensibili, suggerendo come le cellule resistenti siano maggiormente dipendenti da CK2 per la loro sopravvivenza. È inoltre interessante notare che, il trattamento combinato di CX-4945 con imatinib promuove un effetto sinergico sulla riduzione della vitalità delle cellule resistenti all’imatinib in entrambe le linee cellulari di LMC, ripristinando parzialmente l’effetto dell’imatinib. Nelle cellule R-KCL22, è stato anche dimostrato che l’inibizione di CK2 rende le cellule leucemiche sensibili all’azione di altri composti come l’U0126, un inibitore della via di segnale MAPK, e la rapamicina, inibitore specifico del complesso mTORC1. L’associazione ternaria di CX-4945, imatinib e U0126 rappresenta la migliore associazione sinergica capace di ridurre la vitalità delle cellule R-KCL22.
Nel loro insieme, i nostri risultati mettono in luce come CK2 svolga un ruolo da protagonista nelle cellule LMC resistenti all’imatinib e suggeriscono come la chinasi possa rappresentare un promettente bersaglio per lo studio di strategie farmacologiche combinate per il trattamento della LMC nei pazienti resistenti all’imatinib.

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Tipo di EPrint:Tesi di dottorato
Relatore:Donella-Deana, Arianna
Dottorato (corsi e scuole):Ciclo 26 > Scuole 26 > BIOSCIENZE E BIOTECNOLOGIE > BIOCHIMICA E BIOFISICA
Data di deposito della tesi:31 Gennaio 2014
Anno di Pubblicazione:31 Gennaio 2014
Parole chiave (italiano / inglese):protein chinasi CK2 / protein kinase CK2 leucemia mieloide cronica/ chronic myeloid leukemia
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:6822
Depositato il:04 Nov 2014 14:12
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