Enhancing chemosensitivity to gemcitabine via RNA interference targeting the catalytic subunits of protein kinase CK2 in human pancreatic cancer cells

Kreutzer, Jan Nicolas; Ruzzene, Maria; Guerra, Bárbara

doi:10.1186/1471-2407-10-440

Cited by 44 publications

(32 citation statements)

References 37 publications

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“…Indeed, sensitization of pancreatic cancer cells to gemcitabine and head and neck cancer cells to cisplatin by genetic manipulation of CK2 expression has been attributed to resulting suppression of Akt and NF-kB activity, respectively (47,48). Thus it is possible that in addition to the suppression of DNA repair response, CX-4945 enhances activity of gemcitabine and cisplatin by modulating PI3K/Akt and NF-kB signaling.…”

Section: Discussionmentioning

confidence: 99%

CK2 Inhibitor CX-4945 Suppresses DNA Repair Response Triggered by DNA-Targeted Anticancer Drugs and Augments Efficacy: Mechanistic Rationale for Drug Combination Therapy

Siddiqui‐Jain

Bliesath

Macalino

et al. 2012

Molecular Cancer Therapeutics

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Drug combination therapies are commonly used for the treatment of cancers to increase therapeutic efficacy, reduce toxicity, and decrease the incidence of drug resistance. Although drug combination therapies were originally devised primarily by empirical methods, the increased understanding of drug mechanisms and the pathways they modulate provides a unique opportunity to design combinations that are based on mechanistic rationale. We have identified protein kinase CK2 as a promising therapeutic target for combination therapy, because CK2 regulates not just one but many oncogenic pathways and processes that play important roles in drug resistance, including DNA repair, epidermal growth factor receptor signaling, PI3K/AKT/mTOR signaling, Hsp90 machinery activity, hypoxia, and interleukin-6 expression. In this article, we show that CX-4945, a clinical stage selective small molecule inhibitor of CK2, blocks the DNA repair response induced by gemcitabine and cisplatin and synergizes with these agents in models of ovarian cancer. Mechanistic studies show that the enhanced activity is a result of inactivation of XRCC1 and MDC1, two mediator/adaptor proteins that are essential for DNA repair and that require phosphorylation by CK2 for their function. These data position CK2 as a valid pharmacologic target for intelligent drug combinations and support the evaluation of CX-4945 in combination with gemcitabine and platinum-based chemotherapeutics in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

CK2 Inhibitor CX-4945 Suppresses DNA Repair Response Triggered by DNA-Targeted Anticancer Drugs and Augments Efficacy: Mechanistic Rationale for Drug Combination Therapy

Siddiqui‐Jain

Bliesath

Macalino

et al. 2012

Molecular Cancer Therapeutics

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“…In addition, siRNA-mediated knockdown of CK2 catalytic subunits enhanced chemosensitivity to gemcitabine in human pancreatic cancer cells (15). 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).…”

mentioning

confidence: 99%

“…For example, pharmacological inhibition of CK2 kinase activity reverted multidrug resistance of a human T lymphoblastoid cell line (14) at least in part by down-regulating P-glycoprotein activity. In addition, siRNA-mediated knockdown of CK2 catalytic subunits enhanced chemosensitivity to gemcitabine in human pancreatic cancer cells (15). In cells depleted of CK2␣, gemcitabine induced MKK4/JNK signaling, resulting in cell death (15).…”

mentioning

confidence: 99%

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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“…Current studies and clinical trials demonstrate that manipulation of the RNAi mechanism by use of targeted siRNA offers a novel and attractive therapeutic option against cancer (17). There are reports showing that silencing of the IKKε gene by siRNA inhibited invasiveness and growth of breast cancer cells (18) and siRNAs targeting the individual CK2 subunits enhanced chemosensitivity to gemcitabine in human pancreatic cancer cells (19). In our study, the siRNA technology was applied to suppress CHFR expression.…”

Section: Discussionmentioning

confidence: 99%

RNA interference targeting CHFR enhances taxol chemosensitivity in endometrial cancer cells

Wang

Yang

et al. 2012

Oncol Rep

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Abstract. In recent years, it has been reported that CHFR may be a useful biomarker for chemotherapeutic response to microtubule inhibitors in some tumor cells. The purpose of the present study was to test the hypothesis and to elucidate the underlying mechanism in endometrial cancer cells. First, we effectively inhibited CHFR expression at both the mRNA and protein levels using siRNA targeting the CHFR gene in Ishikawa and Hec-1a cells. We found that inhibition of CHFR expression significantly enhanced the cytotoxicity of taxol to both cell types, which was confirmed again by colony formation assays. Moreover, suppression of CHFR induced a significant increase of the mitotic index and much lower numbers of cells at the G 2 /M phase in both cells treated with taxol, indicating mitotic checkpoint impairment. On the other hand, the number of apoptotic cells significantly increased in Ishikawa and Hec-1a cells transfected with CHFR siRNA after treatment with taxol, which was associated with cyclin B1 nuclear localization. Our data indicate that RNA interference targeting CHFR can sensitize endometrial cancer cells to taxol and CHFR may be a promising molecular target to enhance the therapeutic effect of taxol for endometrial cancer.

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Enhancing chemosensitivity to gemcitabine via RNA interference targeting the catalytic subunits of protein kinase CK2 in human pancreatic cancer cells

Cited by 44 publications

References 37 publications

CK2 Inhibitor CX-4945 Suppresses DNA Repair Response Triggered by DNA-Targeted Anticancer Drugs and Augments Efficacy: Mechanistic Rationale for Drug Combination Therapy

CK2 Inhibitor CX-4945 Suppresses DNA Repair Response Triggered by DNA-Targeted Anticancer Drugs and Augments Efficacy: Mechanistic Rationale for Drug Combination Therapy

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

RNA interference targeting CHFR enhances taxol chemosensitivity in endometrial cancer cells

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