Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML): signaling to multidrug-efflux and hyperproliferation

Ld, Cripe; Gelfanov, Vasily; Smith, EA; Dr, Spigel; Ca, Phillips; Gabig, Theodore G.; Jung, Sua; Fyffe, Joanne; Ad, Hartman; Kneebone, Patricia; Mercola, Dan; Burgess, GS; Hs, Boswell

doi:10.1038/sj.leu.2402457

Cited by 51 publications

(44 citation statements)

References 38 publications

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“…Activation of JNK by hematopoietic cytokines, such as IL-3, suppresses growth factor withdrawal-induced cell death in hematopoietic cells, through phosphorylation and inactivation of the prodeath Bcl-2 family protein Bad (Yu et al, 2004). JNK also suppresses cell death in certain tumors (Antonyak et al, 2002;Cripe et al, 2002;She et al, 2002). Based on these observations, it has been proposed that JNK regulates cell death by 'breaking the brake on apoptosis' (Lin, 2003).…”

Section: Rela P50mentioning

confidence: 99%

“…Biochemical characterization and genetic analysis reveal that JNK plays a central role in regulation of many cellular activities, such as proliferation, differentiation, migration, transformation and programmed cell death (apoptosis and necrosis; cell death for the simplicity hereinafter) (Lin, 2006). Deregulation of the JNK activity has been implicated in many human diseases including certain types of cancer (Antonyak et al, 2002;Cripe et al, 2002;She et al, 2002), cardiac hypertrophy and ischemia (He et al, 1999;Nemoto et al, 1998;Sadoshima et al, 2002), immune disorders (Reimold, 2002), liver injury (Uehara et al, 2005), obesity (Hirosumi et al, 2002) and neurodegenerative diseases like Alzheimer's and Parkinson's disease (Xia et al, 2001;Okazawa and Estus, 2002). Not surprisingly, JNK activation is tightly regulated by many cellular regulators or modulators, such as scaffold proteins (Whitmarsh et al, 1998;Ito et al, 1999;McDonald et al, 2000) and MAP phosphatases (Karin, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Wiring the cell signaling circuitry by the NF-κB and JNK1 crosstalk and its applications in human diseases

Liu

Lin

2007

Oncogene

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Integration of the cell signaling circuitry determines the ultimate response of a cell to extracellular stimuli. The transcription factor nuclear factor-kappa B (NF-jB) and mitogen-activated protein kinase JNK1 are major players in the cell signaling circuitry, regulating numerous cellular events and being implicated in the process of many human diseases and certain types of cancer. The interplay between NF-jB and JNK1 provides a paradigm that shows how the crosstalk between different signaling pathways decides the function of the cell signaling circuitry. Understanding the wiring of the cell signaling circuitry may hold the key for cell signaling-based therapy of human diseases.

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Section: Rela P50mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Wiring the cell signaling circuitry by the NF-κB and JNK1 crosstalk and its applications in human diseases

Liu

Lin

2007

Oncogene

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“…6 MAP kinase/ERK kinase (MEK), ERK and JNK/SAPK play a central role in the induction of intracellular activation. [7][8][9] However, both ERK and JNK/SAPK have been found to have different functions depending on experimental conditions, for example, the type of cells investigated or the type and duration of the stimuli. 6,10 .…”

Section: Introductionmentioning

confidence: 99%

Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts

et al. 2003

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MAP kinase/ERK kinase (MEK)-extracellular signal-regulated kinase (ERK) kinases are frequently activated in acute myelogenous leukemia (AML), and can have prosurvival function. The purpose of this study was to induce downmodulation of MEK-ERK activation in AML primary blasts in order to detect the effect on cell cycle progression and on the apoptosis of leukemic cells. We investigated 14 cases of AML with high ERK 1/2 activity and four cases with undetectable or very low activity. After 24 h incubation of the AML blasts with high ERK activity using PD98059 (New England BioLabs, Beverly, MA, USA), a selective inhibitor of MEK1 phosphorylation, at concentrations of 20 and 40 lM, we observed a strong decrease in the levels of ERK1/2 activity. A significant decrease of blast cell proliferation compared with untreated controls was found. In contrast, the proliferation of blast cells that expressed low or undetectable levels of ERK activity was not inhibited. Timecourse analysis demonstrated that the downmodulation of MEK1/2, ERK1 and ERK2 dual-phosphorylation was evident even after 3 h of treatment with 20 and 40 lM. The cleavage of poly(ADP-ribose) polymerase (PARP), an early sign of apoptosis, appeared after 18 h of PD98059 treatment at concentrations of 20 and 40 lM in eight of the 14 cases. After 24 h of treatment, cleaved PARP appeared in all 14 cases. Time-course analysis of cell cycle progression and apoptosis showed that PD98059 induced a G1-phase accumulation with low or undetectable levels of apoptosis after 24 h incubation; after 48 and 72 h incubation, a significant increase of apoptosis was observed. Thus, the primary effect of ERK downmodulation was a cell cycle arrest followed by the apoptosis of a significant percentage of the leukemic blasts. The preclinical model of leukemia treatment reported in this paper makes further comment with regard to MEK1 inhibition as a useful antileukemic target, and encourages the conducting of in vivo studies and clinical investigations.

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“…JNK may play a protective role in some situations (Potapova et al, 1997;Wisdom et al, 1999), and inhibition of JNK2 expression was shown to induce apoptosis of human tumor cell (Potapova et al, 2000). In acute myeloid leukemia cells, multidrug resistance has been related to JNK activity (Potapova et al, 2000;Cripe et al, 2002;Do et al, 2007). Cytarabine induced apoptosis in HL60 cells was preceded by the activation of JNK, but the inhibition of JNK activation did not block apoptosis of HL60 cells by cytarabine (Stadheim et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Influence of Environmental Conditions on c-Jun N-terminal Kinase Mediated Apoptosis of HL60 Cells by Anti-Cancer Drugs

Hur

Kang

Kim

et al. 2010

Biomolecules and Therapeutics

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-Activation of JNK has long been associated with the apoptotic response induced by various anti-cancer drugs including doxorubicin, vinblastine, and etoposide. In this study, we examined and compared patterns of apoptosis and JNK activation according to three different anti-cancer drugs (daunorubicin, vinblastine, and etoposide) and two different sources of HL60 cells (Jackson Laboratory and ATCC). HL60 cells from Jackson Laboratory (HL60/RPMI) were maintained in RPMI 1640 containing 5% fetal bovine serum and those from ATCC (HL60/IMDM) in IMDM containing 20% fetal bovine serum as to each manufacture's guideline. In general, HL60/RPMI cells were more sensitive to anti-cancer drugs compared to HL60/IMDM cells, demonstrated by the XTT and flow cytometric analyses. Apoptotic pathways after treatment with anti-cancer drugs seemed to be different between HL60/RPMI (daunorubicin and etoposide, caspase 3 dependent, but caspase 8 or 9 independent; vinblastine, caspase 3 independent) and HL60/IMDM (caspase 3 and caspase 9 dependent). The expression of apoptotic protein, BID, was consistent with caspase 3 activation. Immunoblotting of phospho-JNK and JNK kinase assay showed JNK activation by all three anti-cancer drugs in HL60/RPMI, while JNK activation was observed only in vinblastine-treated cells in HL60/IMDM. Our study results suggest that in vitro environmental conditions have a significant influence on JNK mediated apoptosis of HL60 cells by anti-cancer drugs and in vitro culture conditions are important factors in JNK or possibly other MAPK related studies.

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Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML): signaling to multidrug-efflux and hyperproliferation

Cited by 51 publications

References 38 publications

Wiring the cell signaling circuitry by the NF-κB and JNK1 crosstalk and its applications in human diseases

Wiring the cell signaling circuitry by the NF-κB and JNK1 crosstalk and its applications in human diseases

Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts

Influence of Environmental Conditions on c-Jun N-terminal Kinase Mediated Apoptosis of HL60 Cells by Anti-Cancer Drugs

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