Aberrant signalling by protein kinase CK2 in imatinib‐resistant chronic myeloid leukaemia cells: Biochemical evidence and therapeutic perspectives

Borgo, Christian; Cesaro, Luca; Salizzato, Valentina; Ruzzene, Maria; Massimino, Maria Lina; Pinna, Lorenzo A.; Donella‐Deana, Arianna

doi:10.1016/j.molonc.2013.08.006

Cited by 33 publications

(47 citation statements)

References 42 publications

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“…The equivalent effects on vemurafenib responses of kinase-intact and kinase-inactive CK2␣ that we observed argue that the kinase activity is not important in the vemurafenib response of BRAF mutant melanoma, but it is certainly possible that other genetic differences may also affect the relative roles of catalytic activity versus protein-protein interactions. Our study differs from work by Borgo et al (16), who found a kinase-dependent role of CK2 in imatinib-resistant chronic myeloid leukemia. These differences may reflect the divergent genetic and epigenetic contexts of BCR-ABL mutant chronic myeloid leukemia versus BRAF mutant melanomas.…”

Section: Discussioncontrasting

confidence: 99%

“…In cells depleted of CK2␣, gemcitabine induced MKK4/JNK signaling, resulting in cell death (15). Furthermore, CK2 displayed elevated protein expression and activity in chronic myeloid leukemia cells that are resistant to the small molecule kinase inhibitor imatinib (16). Either reduction of CK2␣ expression or pharmacological inhibition of CK2␣ kinase activity restored imatinib sensitivity, possibly through suppressing Akt activity (16).…”

mentioning

confidence: 99%

“…Furthermore, CK2 displayed elevated protein expression and activity in chronic myeloid leukemia cells that are resistant to the small molecule kinase inhibitor imatinib (16). Either reduction of CK2␣ expression or pharmacological inhibition of CK2␣ kinase activity restored imatinib sensitivity, possibly through suppressing Akt activity (16). However, the role of CK2␣ in drug resistance, particularly to targeted therapeutics, has remained underexplored.…”

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confidence: 99%

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Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma

Zhou¹,

Ritt

Morrison

et al. 2016

Journal of Biological Chemistry

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The protein kinase casein kinase 2 (CK2) is a pleiotropic and constitutively active kinase that plays crucial roles in cellular proliferation and survival. Overexpression of CK2, particularly the ␣ catalytic subunit (CK2␣, CSNK2A1), has been implicated in a wide variety of cancers and is associated with poorer survival and resistance to both conventional and targeted anticancer therapies. Here, we found that CK2␣ protein is elevated in melanoma cell lines compared with normal human melanocytes. We then tested the involvement of CK2␣ in drug resistance to Food and Drug Administrationapproved single agent targeted therapies for melanoma. In BRAF mutant melanoma cells, ectopic CK2␣ decreased sensitivity to vemurafenib (BRAF inhibitor), dabrafenib (BRAF inhibitor), and trametinib (MEK inhibitor) by a mechanism distinct from that of mutant NRAS. Conversely, knockdown of CK2␣ sensitized cells to inhibitor treatment. CK2␣-mediated RAF-MEK kinase inhibitor resistance was tightly linked to its maintenance of ERK phosphorylation. We found that CK2␣ post-translationally regulates the ERK-specific phosphatase dual specificity phosphatase 6 (DUSP6) in a kinase dependent-manner, decreasing its abundance. However, we unexpectedly showed, by using a kinase-inactive mutant of CK2␣, that RAF-MEK inhibitor resistance did not rely on CK2␣ kinase catalytic function, and both wild-type and kinase-inactive CK2␣ maintained ERK phosphorylation upon inhibition of BRAF or MEK. That both wild-type and kinase-inactive CK2␣ bound equally well to the RAF-MEK-ERK scaffold kinase suppressor of Ras 1 (KSR1) suggested that CK2␣ increases KSR facilitation of ERK phosphorylation. Accordingly, CK2␣ did not cause resistance to direct inhibition of ERK by the ERK1/2-selective inhibitor SCH772984. Our findings support a kinase-independent scaffolding function of CK2␣ that promotes resistance to RAF-and MEK-targeted therapies.The protein kinase casein kinase 2 or II (CK2) 2 is a highly conserved, ubiquitously expressed, pleiotropic, and constitutively active serine/threonine kinase that has crucial roles in cell survival, proliferation, and differentiation (2-4). The CK2 holoenzyme consists of two regulatory (␤) and two catalytic (␣ or ␣Ј) subunits, the latter of which can also function independently of the tetramer (5). Although CK2 itself does not appear to be a proto-oncogene, its up-regulation has been shown to promote growth and prevent apoptosis, both of which promote cancer (4). Indeed, overexpression of CK2 at the transcript and/or protein level has been observed in many cancers (6), including multiple myeloma (7), chronic lymphocytic leukemia (8), breast cancer (9), colorectal cancer (10), liver cancer (11), etc. and is correlated with poorer patient survival (6, 10, 12). Similarly, CK2 exhibited 2.5-fold higher catalytic activity in metastatic melanoma than in dermal nevi (13).In addition to its roles in tumor growth and progression, CK2 also promotes drug resistance to both conventional and targeted therapeutics. For example, pharmacological ...

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Section: Discussioncontrasting

confidence: 99%

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confidence: 99%

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confidence: 99%

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Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma

Zhou¹,

Ritt

Morrison

et al. 2016

Journal of Biological Chemistry

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“…[32][33][34][35] Importantly, it was clearly demonstrated that BCR-ABL/CKII complex plays an essential role in the regulation of imatinib resistance. 36 To verify whether PTEN tail phosphorylation is regulated by BCR-ABL, the BCR-ABL inhibitor imatinib and/or the casein kinase inhibitor TBB were utilized in BCR-ABL expressing NIH3T3 cells and PTEN phosphorylation levels were assessed by western immunoblot, upon normalization of PTEN levels. As shown in Figure 2A, the association Imatinib and TBB revert PTEN tail phosphorylation induced by BCR-ABL.…”

Section: Cd34mentioning

confidence: 99%

“…2C). 32,34,36 Next, to determine whether BCR-ABL mediates PTEN phosphorylation by Casein Kinase II, we performed an in vitro kinase assay with purified ABL protein and with PTEN and CKII immunoprecipitated proteins, as described in Material and Methods. As shown in Figure 2D, the presence of ABL increases PTEN phosphorylation induced by CKII.…”

Section: Cd34mentioning

confidence: 99%

BCR-ABL inactivates cytosolic PTEN through Casein Kinase II mediated tail phosphorylation

Morotti¹,

Panuzzo²,

Crivellaro³

et al. 2015

Cell Cycle

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The tumor suppressive function of PTEN is exerted within 2 different cellular compartments. In the cytosolmembrane, it negatively regulates PI3K-AKT pathway through the de-phosphorylation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), therefore blocking one of the major signaling transduction pathways in tumorigenesis. In the nucleus, PTEN controls genomic stability and cellular proliferation through phosphatase independent mechanisms. Importantly, impairments in PTEN cellular compartmentalization, changes in protein levels and post-transductional modifications affect PTEN tumor suppressive functions. Targeting mechanisms that inactivate PTEN promotes apoptosis induction of cancer cells, without affecting normal cells, with appealing therapeutic implications. Recently, we have shown that BCR-ABL promotes PTEN nuclear exclusion by favoring HAUSP mediated PTEN de-ubiquitination in Chronic Myeloid Leukemia. Here, we show that nuclear exclusion of PTEN is associated with PTEN inactivation in the cytoplasm of CML cells. In particular, BCR-ABL promotes Casein Kinase II-mediated PTEN tail phosphorylation with consequent inhibition of the phosphatase activity toward PIP3. Targeting Casein Kinase II promotes PTEN reactivation with apoptosis induction. We therefore propose a novel BCR-ABL/CKII/PTEN pathway as a potential target to achieve synthetic lethality with tyrosine kinase inhibitors.

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Targeting CK2 for Cancer Therapy Using a Nanomedicine Approach

Ahmed

Unger

Kren

et al. 2015

Protein Kinase CK2 Cellular Function in Normal and Disease States

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CK2 is a signal-responsive serine/threonine protein kinase which promotes cell proliferation, suppresses apoptosis, and demonstrates increased expression in numerous cancers. Here, we present information on investigations into CK2-focused cancer therapy in general and discuss in detail a nanomedicine approach to targeting CK2 in a cancer cell-specifi c manner. Specifi cally, we summarize data on biodistribution and therapeutic effi cacy of a tenfi bgen (TBG) nanoencapsulation technology for the delivery of anti-CK2 cargos to malignant cells. The TBG nanocapsule cargos discussed include siRNA (siCK2), single-stranded DNA/RNA chimeric oligonucleotides (RNAi-CK2), and a small-molecule CK2 inhibitor (DMAT). Systemic administration of TBG-RNAi-CK2 resulted in xenograft tumor reduction using low doses with concomitant reduction in CK2 protein expression. Systemic TBG-DMAT treatment decreased xenograft tumor proliferation. No toxicity or early infl ammation response was observed after using any of the TBG encapsulated anti-CK2 cargos. The utility of this therapy approach for targeting metastatic cancer sites and on overall survival is also discussed. Protected and malignant cell-specifi c delivery of a therapeutic is a promising target-specifi c and versatile approach for cancer therapy, and both the TBG encapsulation technology and the anti-CK2 oligonucleotide approach demonstrate substantial potential for the treatment of malignancy.

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Aberrant signalling by protein kinase CK2 in imatinib‐resistant chronic myeloid leukaemia cells: Biochemical evidence and therapeutic perspectives

Cited by 33 publications

References 42 publications

Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma

Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma

BCR-ABL inactivates cytosolic PTEN through Casein Kinase II mediated tail phosphorylation

Targeting CK2 for Cancer Therapy Using a Nanomedicine Approach

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