Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity

Laura Quotti Tubi, Carmela Gurrieri, Alessandra Brancalion, Laura Bonaldi, Roberta Bertorelle, Sabrina Manni, Laura Pavan, Federica Lessi, Renato Zambello, Livio Trentin, Fausto Adami, Maria Ruzzene, Lorenzo A. Pinna, Gianpietro Semenzato, Francesco Piazza

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Abstract

Background: The involvement of protein kinase CK2 in sustaining cancer cell survival could have implications also in the resistance to conventional and unconventional therapies. Moreover, CK2 role in blood tumors is rapidly emerging and this kinase has been recognized as a potential therapeutic target. Phase I clinical trials with the oral small ATP-competitive CK2 inhibitor CX-4945 are currently ongoing in solid tumors and multiple myeloma. Methods. We have analyzed the expression of CK2 in acute myeloid leukemia and its function in cell growth and in the response to the chemotherapeutic agent daunorubicin We employed acute myeloid leukemia cell lines and primary blasts from patients grouped according to the European LeukemiaNet risk classification. Cell survival, apoptosis and sensitivity to daunorubicin were assessed by different means. p53-dependent CK2-inhibition-induced apoptosis was investigated in p53 wild-type and mutant cells. Results: CK2α was found highly expressed in the majority of samples across the different acute myeloid leukemia prognostic subgroups as compared to normal CD34§ssup§+§esup§ hematopoietic and bone marrow cells. Inhibition of CK2 with CX-4945, K27 or siRNAs caused a p53-dependent acute myeloid leukemia cell apoptosis. CK2 inhibition was associated with a synergistic increase of the cytotoxic effects of daunorubicin. Baseline and daunorubicin-induced STAT3 activation was hampered upon CK2 blockade. Conclusions: These results suggest that CK2 is over expressed across the different acute myeloid leukemia subsets and acts as an important regulator of acute myeloid leukemia cell survival. CK2 negative regulation of the protein levels of tumor suppressor p53 and activation of the STAT3 anti-apoptotic pathway might antagonize apoptosis and could be involved in acute myeloid leukemia cell resistance to daunorubicin.

Original languageEnglish
Article number78
JournalJournal of Hematology and Oncology
Volume6
Issue number1
DOIs
Publication statusPublished - 2013

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Casein Kinase II
Daunorubicin
Myeloid Cells
RNA Interference
Acute Myeloid Leukemia
Cell Survival
Adenosine Triphosphate
Apoptosis
Tumor Suppressor Protein p53
Neoplasms
Clinical Trials, Phase I
5-(3-chlorophenylamino)benzo(c)(2,6)naphthyridine-8-carboxylic acid
Multiple Myeloma
Bone Marrow Cells
Phosphotransferases
Cell Line
Therapeutics
Growth

Keywords

  • Acute myeloid leukemia
  • Apoptosis
  • CX-4945
  • Daunorubicin
  • Kinase inhibitors
  • p53
  • Protein kinase CK2
  • STAT3

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research
  • Molecular Biology

Cite this

Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity. / Quotti Tubi, Laura; Gurrieri, Carmela; Brancalion, Alessandra; Bonaldi, Laura; Bertorelle, Roberta; Manni, Sabrina; Pavan, Laura; Lessi, Federica; Zambello, Renato; Trentin, Livio; Adami, Fausto; Ruzzene, Maria; Pinna, Lorenzo A.; Semenzato, Gianpietro; Piazza, Francesco.

In: Journal of Hematology and Oncology, Vol. 6, No. 1, 78, 2013.

Research output: Contribution to journalArticle

Quotti Tubi, Laura ; Gurrieri, Carmela ; Brancalion, Alessandra ; Bonaldi, Laura ; Bertorelle, Roberta ; Manni, Sabrina ; Pavan, Laura ; Lessi, Federica ; Zambello, Renato ; Trentin, Livio ; Adami, Fausto ; Ruzzene, Maria ; Pinna, Lorenzo A. ; Semenzato, Gianpietro ; Piazza, Francesco. / Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity. In: Journal of Hematology and Oncology. 2013 ; Vol. 6, No. 1.
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abstract = "Background: The involvement of protein kinase CK2 in sustaining cancer cell survival could have implications also in the resistance to conventional and unconventional therapies. Moreover, CK2 role in blood tumors is rapidly emerging and this kinase has been recognized as a potential therapeutic target. Phase I clinical trials with the oral small ATP-competitive CK2 inhibitor CX-4945 are currently ongoing in solid tumors and multiple myeloma. Methods. We have analyzed the expression of CK2 in acute myeloid leukemia and its function in cell growth and in the response to the chemotherapeutic agent daunorubicin We employed acute myeloid leukemia cell lines and primary blasts from patients grouped according to the European LeukemiaNet risk classification. Cell survival, apoptosis and sensitivity to daunorubicin were assessed by different means. p53-dependent CK2-inhibition-induced apoptosis was investigated in p53 wild-type and mutant cells. Results: CK2α was found highly expressed in the majority of samples across the different acute myeloid leukemia prognostic subgroups as compared to normal CD34§ssup§+§esup§ hematopoietic and bone marrow cells. Inhibition of CK2 with CX-4945, K27 or siRNAs caused a p53-dependent acute myeloid leukemia cell apoptosis. CK2 inhibition was associated with a synergistic increase of the cytotoxic effects of daunorubicin. Baseline and daunorubicin-induced STAT3 activation was hampered upon CK2 blockade. Conclusions: These results suggest that CK2 is over expressed across the different acute myeloid leukemia subsets and acts as an important regulator of acute myeloid leukemia cell survival. CK2 negative regulation of the protein levels of tumor suppressor p53 and activation of the STAT3 anti-apoptotic pathway might antagonize apoptosis and could be involved in acute myeloid leukemia cell resistance to daunorubicin.",
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AU - Quotti Tubi, Laura

AU - Gurrieri, Carmela

AU - Brancalion, Alessandra

AU - Bonaldi, Laura

AU - Bertorelle, Roberta

AU - Manni, Sabrina

AU - Pavan, Laura

AU - Lessi, Federica

AU - Zambello, Renato

AU - Trentin, Livio

AU - Adami, Fausto

AU - Ruzzene, Maria

AU - Pinna, Lorenzo A.

AU - Semenzato, Gianpietro

AU - Piazza, Francesco

PY - 2013

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N2 - Background: The involvement of protein kinase CK2 in sustaining cancer cell survival could have implications also in the resistance to conventional and unconventional therapies. Moreover, CK2 role in blood tumors is rapidly emerging and this kinase has been recognized as a potential therapeutic target. Phase I clinical trials with the oral small ATP-competitive CK2 inhibitor CX-4945 are currently ongoing in solid tumors and multiple myeloma. Methods. We have analyzed the expression of CK2 in acute myeloid leukemia and its function in cell growth and in the response to the chemotherapeutic agent daunorubicin We employed acute myeloid leukemia cell lines and primary blasts from patients grouped according to the European LeukemiaNet risk classification. Cell survival, apoptosis and sensitivity to daunorubicin were assessed by different means. p53-dependent CK2-inhibition-induced apoptosis was investigated in p53 wild-type and mutant cells. Results: CK2α was found highly expressed in the majority of samples across the different acute myeloid leukemia prognostic subgroups as compared to normal CD34§ssup§+§esup§ hematopoietic and bone marrow cells. Inhibition of CK2 with CX-4945, K27 or siRNAs caused a p53-dependent acute myeloid leukemia cell apoptosis. CK2 inhibition was associated with a synergistic increase of the cytotoxic effects of daunorubicin. Baseline and daunorubicin-induced STAT3 activation was hampered upon CK2 blockade. Conclusions: These results suggest that CK2 is over expressed across the different acute myeloid leukemia subsets and acts as an important regulator of acute myeloid leukemia cell survival. CK2 negative regulation of the protein levels of tumor suppressor p53 and activation of the STAT3 anti-apoptotic pathway might antagonize apoptosis and could be involved in acute myeloid leukemia cell resistance to daunorubicin.

AB - Background: The involvement of protein kinase CK2 in sustaining cancer cell survival could have implications also in the resistance to conventional and unconventional therapies. Moreover, CK2 role in blood tumors is rapidly emerging and this kinase has been recognized as a potential therapeutic target. Phase I clinical trials with the oral small ATP-competitive CK2 inhibitor CX-4945 are currently ongoing in solid tumors and multiple myeloma. Methods. We have analyzed the expression of CK2 in acute myeloid leukemia and its function in cell growth and in the response to the chemotherapeutic agent daunorubicin We employed acute myeloid leukemia cell lines and primary blasts from patients grouped according to the European LeukemiaNet risk classification. Cell survival, apoptosis and sensitivity to daunorubicin were assessed by different means. p53-dependent CK2-inhibition-induced apoptosis was investigated in p53 wild-type and mutant cells. Results: CK2α was found highly expressed in the majority of samples across the different acute myeloid leukemia prognostic subgroups as compared to normal CD34§ssup§+§esup§ hematopoietic and bone marrow cells. Inhibition of CK2 with CX-4945, K27 or siRNAs caused a p53-dependent acute myeloid leukemia cell apoptosis. CK2 inhibition was associated with a synergistic increase of the cytotoxic effects of daunorubicin. Baseline and daunorubicin-induced STAT3 activation was hampered upon CK2 blockade. Conclusions: These results suggest that CK2 is over expressed across the different acute myeloid leukemia subsets and acts as an important regulator of acute myeloid leukemia cell survival. CK2 negative regulation of the protein levels of tumor suppressor p53 and activation of the STAT3 anti-apoptotic pathway might antagonize apoptosis and could be involved in acute myeloid leukemia cell resistance to daunorubicin.

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