Inhibition of MEK signaling enhances the ability of cytarabine to induce growth arrest and apoptosis of acute myelogenous leukemia cells

Nishioka, Chie; Ikezoe, Takayuki; Yang, Jing; Yokoyama, Akihito

doi:10.1007/s10495-009-0372-4

Cited by 31 publications

(27 citation statements)

References 38 publications

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“…It has also been demonstrated that there are synergistic or additive effects of MEK inhibitors in combination with various cytotoxic chemotherapeutic agents. In vitro studies using leukemia cell lines have reported that MEK inhibitors enhance the cytotoxic effects of cytarabine or doxorubicin [43, 44]. Similar enhanced effects of MEK inhibitors in combination with cytotoxic drugs have been observed in xenograft tumor models of solid cancers including melanoma, [45] and biliary, [46] colon, [47, 48] lung, [48] pancreatic [48] or hepatocellular carcinoma [49].…”

Section: Discussionmentioning

confidence: 81%

Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells

et al. 2017

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Primary or acquired resistance to MEK inhibitors has been a barrier to successful treatment with MEK inhibitors in many tumors. In this study, we analyzed genome-wide gene expression profiling data from 6 sensitive and 6 resistant cell lines to identify candidate genes whose expression changes are associated with responses to a MEK inhibitor, selumetinib (AZD6244). Of 62 identified differentially expressed genes, we selected Immunoglobulin Transcription Factor 2, also known as transcription factor 4 as a potential drug resistance marker for further analysis. This was because the ITF-2 expression increase in resistant cell lines was relatively high and a previous study has suggested that ITF-2 functions as an oncogene in human colon cancers. We also established an AZD6244 resistant cell line (M14/AZD-3) from an AZD6244 sensitive M14 cell line. The expression of the ITF-2 was elevated both in primary AZD6244 resistant cell line, LOX-IMVI and acquired resistant cell line, M14/AZD-3. Targeted silencing of ITF-2 by siRNA significantly enhanced susceptibility to AZD6244 in resistant cells. Wnt/β-catenin pathway was activated through direct interaction of p-ERK and GSK3β. Our results suggest that up-regulation of the ITF-2 gene expression is associated with cellular resistance to MEK inhibitors, and activation of Wnt signaling pathway through interaction of p-ERK and GSK3β seems to be a mechanism for increase of ITF-2.

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Section: Discussionmentioning

confidence: 81%

Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells

et al. 2017

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“…49 Moreover, simultaneous disruption of Chk1 and MEK/ERK pathways induces selective toxicity in human leukemia and MM cells. 50,51 However, the mechanisms by which MEK/ERK pathway disruption potentiates DNA damage triggered by Chk1 inhibitors is not yet delineated. Here, we observed that SIRT6 directly controls cell proliferation and genomic stability of MM cells by modulating ERK-signaling-related genes; conversely, SIRT6 depletion triggers activation of ERK/p90RSK signaling and Chk1 inhibition, which confers sensitization to genotoxic stress both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells

Cea

Cagnetta

Adamia

et al. 2016

Blood

101

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Key Points• SIRT6 is highly expressed in multiple myeloma cells and blocks expression of ERKregulated genes.• Targeting SIRT6 enzymatic activity sensitizes multiple myeloma cells to DNAdamaging agents.Multiple myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here, we show that the NAD 1 -dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response to genomic stability, and that high SIRT6 levels are associated with adverse prognosis. Mechanistically, SIRT6 interacts with the transcription factor ELK1 and with the ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of mitogen-activated protein kinase (MAPK) pathway genes, MAPK signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and confers resistance to DNA damage. Using genetic and biochemical studies in vitro and in human MM xenograft models, we show that SIRT6 depletion both enhances proliferation and confers sensitization to DNA-damaging agents. Our findings therefore provide insights into the functional interplay between SIRT6 and DNA repair mechanisms, with implications for both tumorigenesis and the treatment of MM. (Blood. 2016;127(9):1138-1150 IntroductionGenomic instability is a common feature of monoclonal gammopathies, resulting in complex genetic changes associated with disease progression from monoclonal gammopathy of undetermined significance to active multiple myeloma (MM) to plasma cell leukemia.1,2 Although alterations in DNA damage checkpoint proteins are less common (10% to 15%) in blood cancers compared with solid tumors, [3][4][5] MM cells do manifest a dysfunctional DNA-damage response (DDR), a key determinant of their genomic instability. [6][7][8] Identifying proteins and signaling pathways that protect MM cells from cumulative genomic instability may therefore lead to innovative therapeutic opportunities, as exemplified by the clinical efficacy of PARP inhibitors in the context of breast and ovarian tumors lacking functional BRCA1 or BRCA2. 9,10 In MM cells, direct evidence of homozygous loss or mutations in BRCA1/2 or other DDR genes is lacking, but increased DNA repair activity has been reported. 11,12 Thus, identification of adaptive pathways for coping with genomic instability in MM may similarly provide the framework for new therapeutic strategies. Sirtuins (SIRTs) are NAD1 -degrading enzymes involved in a variety of biological processes, ranging from metabolism to lifespan regulation. 13,14 Of the 7 sirtuin family members, only SIRT6 clearly contributes to DNA repair. [15][16][17][18] Consistently, murine SIRT6 knockout cells exhibit genomic instability and hypersensitivity to DNA-damaging agents. 15,17,19 Moreover...

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“…Our study suggests that CCN1 regulates Bcl-xL, c-Myc, and Bax and acts as a tumor promoter through the MEK/ERK pathway. MEK/ERK inhibition enhances the response of AML cells to several chemical treatments [46]-[50], including cytarabine [51]; therefore, we hypothesize that inhibiting CCN1 increases the cytarabine-induced apoptosis of AML cells by down-regulating the MEK/ERK signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting CCN1 blocks AML cell growth by disrupting the MEK/ERK pathway

Niu

Zhao

et al. 2014

Cancer Cell Int

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BackgroundCCN1 plays distinct roles in various tumor types, but little is known regarding the role of CCN1 in leukemia.MethodsWe analyzed CCN1 protein expression in leukemia cell lines and in AML bone marrow samples. We also evaluated the effects of antibody- or siRNA-mediated inhibition of CCN1 on the growth of two AML cell lines (U937 and Kasumi-1 cells) and on the MEK/ERK pathway, β-catenin and other related genes.ResultsU937 and Kasumi-1 cells had markedly higher CCN1 expression than the 5 other leukemia cell lines, and CCN1 protein expression was higher in the AML bone marrow samples than in the normal bone marrow samples. Blocking CCN1 with an antibody in U937 and Kasumi-1 cells suppressed proliferation, increased apoptosis, down-regulated Bcl-xL and c-Myc expression, up-regulated Bax expression, and had no effect on Survivin. siRNA-mediated down-regulation of CCN1 inhibited the proliferation and colony formation of U937 and Kasumi-1 cells and increased cytarabine-induced apoptosis. Furthermore, CCN1 siRNA reduced MEK and ERK phosphorylation without affecting β-catenin; the CCN1 antibody similarly affected MEK and ERK phosphorylation. These changes in phosphorylation could influence the expression of Bcl-xL, c-Myc and Bax in AML cells.ConclusionsThe data suggested that CCN1 is a tumor promoter in AML that acts through the MEK/ERK pathway to up-regulate c-Myc and Bcl-xL and to down-regulate Bax.

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Inhibition of MEK signaling enhances the ability of cytarabine to induce growth arrest and apoptosis of acute myelogenous leukemia cells

Cited by 31 publications

References 38 publications

Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells

Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells

Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells

Inhibiting CCN1 blocks AML cell growth by disrupting the MEK/ERK pathway

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