Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c-Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c-Abl. Indeed, c-Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c-Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia-derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c-Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c-Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act.
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PMID:c-Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin-based therapy. 1789 73

Over-expression of two members of MAP kinase family (JNK2 and p38) has been already observed in chronic myeloid leukemia (CML). In the present study, significance of this deregulation was investigated. Impacts of JNK2/p38 suppression on gene expression profile of CML cell lines (K562/KU-812) were studied using an experimental approach that combines siRNA-mediated specific inhibition of the genes and array-based expression analyses. After JNK2 depletion, 27 out of 588 tested genes showed significant expression changes, with 13 down-regulated genes and 14 up-regulated genes. Among others, expression of MSH2 and MSH6, mdm2, and caspase-2 was reduced and, on the other hand, MKK1 and MKK6, RFC2, cytokeratins K18 and K19, BAD, and DR5 expression was up-regulated. In the case of p38 silencing, 20 genes were considered as significantly deregulated (7 genes reduced, 13 over-expressed). These genes included caspase-10, SOD1, and Notch4 (down-regulation) and caspase-2 and caspase-3, CDC2, CDK4, and c-kit (up-regulation). In conclusion, comparison of expression profiles after JNK2 or p38 gene silencing revealed distinct sets of affected genes. The results implied an unequal impact of the MAPK deregulation on the CML cells. Further, we demonstrated that neither JNK2 nor p38 siRNAmediated inhibition led to significant change of CML cell proliferation. It suggests that there are other important, likely upstream regulators essential for CML malignant cell growth/transformation; therefore, separate inhibition of JNK2 or p38 MAPK gene is not sufficient for a proliferation arrest.
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PMID:JNK2 and p38 MAPK over-expressions do not represent key events in chronic myeloid leukemia transformation. 1794 34

RAC3 belongs to the family of p160 nuclear receptors coactivators and it is over-expressed in several tumors. We have previously shown that RAC3 is a NF-kappaB coactivator. In this paper, we investigated the role of RAC3 in cell-sensitivity to apoptosis, using H2O2 in the human embryonic kidney cell line (HEK293), and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in a human chronic myeloid leukemia cell line (K562) naturally resistant to TRAIL. We observed that the tumoral K562 cells have high levels of RAC3 if compared with the non-tumoral HEK293 cells. The normal or transfected coactivator over-expression inhibits apoptosis through a diminished caspase activity and AIF nuclear translocation, increased NF-kappaB, AKT and p38, and decreased ERK activities. In contrast, inhibition of RAC3 by siRNA induced sensitivity of K562 to TRAIL-induced apoptosis. Such results suggest that over-expression of RAC3 contributes to tumor development through molecular mechanisms that do not depend strictly on acetylation and/or steroid hormones, which control cell death. This could be a possible target for future tumor therapies.
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PMID:[RAC3 nuclear receptor co-activator has a protective role in the apoptosis induced by different stimuli]. 1805 Dec 30

This study examined the signaling events induced by shikonin that lead to the induction of apoptosis in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells (e.g., K562, LAMA84). Treatment of K562 cells with shikonin (e.g., 0.5 muM) resulted in profound induction of apoptosis accompanied by rapid generation of reactive oxygen species (ROS), striking activation of c-Jun-N-terminal kinase (JNK) and p38, marked release of the mitochondrial proteins cytochrome c and Smac/DIABLO, activation of caspase-9 and -3, and cleavage of PARP. Scavenging of ROS completely blocked all of the above-mentioned events (i.e., JNK and p38 phosphorylation, cytochrome c and Smac/DIABLO release, caspase and PARP cleavage, as well as the induction of apoptosis) following shikonin treatment. Inhibition of JNK and knock-down of JNK1 significantly attenuated cytochrome c release, caspase cleavage and apoptosis, but did not affect shikonin-mediated ROS production. Additionally, inhibition of caspase activation completely blocked shikonin-induced apoptosis, but did not appreciably modify shikonin-mediated cytochrome c release or ROS generation. Altogether, these findings demonstrate that shikonin-induced oxidative injury operates at a proximal point in apoptotic signaling cascades, and subsequently activates the stress-related JNK pathway, triggers mitochondrial dysfunction, cytochrome c release, and caspase activation, and leads to apoptosis. Our data also suggest that shikonin may be a promising agent for the treatment of CML, as a generator of ROS.
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PMID:Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells. 1866 79

Methylglyoxal is a reactive dicarbonyl compound generated as an intermediate of glycolysis during the physical glycation in the diabetic condition. It is considered to be a potent precursor of advanced glycation end products (AGEs) formation. Methylglyoxal itself and methylglyoxal-derived AGEs have been commonly implicated in the development of diabetic neuropathy. Our previous study indicated that vanillic acid showed an inhibitory effect against methylglyoxal-mediated Neuro-2A cell apoptosis, suggesting that vanillic acid might possess cytoprotective properties in the prevention of diabetic neuropathy complication. In this study, the effects of vanillic acid on the methylglyoxal-mediated glycation system involved in the progression of Neuro-2A cell apoptosis were further investigated. Our findings indicated that methylglyoxal-induced Neuro-2A cell apoptosis was mediated through the possible glycation mechanism of oxidative stress, activation of the MAPK signaling pathway (p38 and JNK) and oxidation-sensitive protein expression (PKC and p47(phox)) and methylglyoxal-derived N-epsilon-(carboxymethyl)lysine (CML) formation. Vanillic acid, however, suppressed methylglyoxal-induced Neuro-2A cell apoptosis via inhibition of glycation mechanisms including ROS, p38 and JNK, PKC and p47(phox), and methylglyoxal-derived CML formation. In the present study, we established the first evidence that vanillic acid might contribute to the prevention of the development of diabetic neuropathy by blocking the methylglyoxal-mediated intracellular glycation system.
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PMID:Inhibitory effect of vanillic acid on methylglyoxal-mediated glycation in apoptotic Neuro-2A cells. 1870 41

Ceramide is a sphingolipid that activates stress kinases such as p38 and c-JUN N-Terminal Kinase (JNK). Though Chronic Myelogenous Leukemia (CML) derived K562 cells resist killing by short chain C2-ceramide, we report here that longer chain C6-ceramide promotes apoptosis in these cells. C6-ceramide induces cleavage of Caspase-8 and Caspase-9, but only Caspase-8 is required for apoptosis. The sphingolipid killed CML derived KBM5 cells and, to a lesser extent, imatinib-resistant KBM5-STI cells suggesting that BCR-ABL can not completely block C6-ceramide-induced apoptosis but the kinase may regulate the process. BCR-ABL is known to suppress Protein Phosphatase 2A (PP2A) in CML cells. While C6-ceramide can activate PP2A in acute leukemia cells, the sphingolipid did not activate the phosphatase in K562 cells. C6-ceramide did not activate p38 kinase but did promote JNK activation and phosphorylation of JUN. Inhibition of JNK by pharmacological agent protected K562 cells from C6-ceramide suggesting that JNK plays an essential role in C6-ceramide mediated apoptosis. Furthermore, the sphingolipid promoted MCL-1 phosphorylation by a mechanism that, at least in part, involves JNK. The findings presented here suggest that Caspase-8, JNK, and perhaps MCL-1 may play important roles in regulating cell death and may represent new targets for therapeutic strategies for CML.
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PMID:Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNK. 1894 50

Heat shock response is an adaptive response, which helps the cells to regulate their physiological homeostasis under stress. Here we show that the natural compound curcumin induces nuclear translocation of the heat shock transcription factor (HSF)-1, its binding to a heat shock regulatory element (HSE), and the subsequent activation of the hsp70 promoter through the extracellular regulated kinase (ERK)/mitogen activated protein (MAP) ERK (MEK) and c-jun N-terminal kinase (JNK) pathways, but not through p38. We observe that curcumin activates hsp70A and hsp70B mRNA transcription, increases HSP protein expression but decreases the expression of Bag-1, a Hsp70 co-chaperone in K562 cells. This induction Hsp70 protein expression goes in line with the anti-inflammatory and anti-proliferative properties of curcumin in chronic myelogenous leukemia.
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PMID:Induction of heat shock response by curcumin in human leukemia cells. 1924 53

Bcr-abl signals for leukemogenesis of chronic myeloid leukemia (CML) and activates ras. Since the function of promyelocytic leukemia protein (pml) is provoked by ras to promote apoptosis and senescence in untransformed cells, the function is probably masked in CML. Imatinib specifically inhibits bcr-abl and induces apoptosis of CML cells. As reported previously, p53(wild) CML was more resistant to imatinib than that lacking p53. Here, we searched for an imatinib-induced p53 independent proapoptotic mechanism. We found imatinib up-regulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73; expression of pml and bax; formation of PML-nuclear body (NB); and co-localization of TAp73/PML-NB in p53-nonfunctioning K562 and p53(mutant) Meg-01 CML cells, but not in BCR-ABL(-) HL60 cells. In K562 cells, with short interfering RNAs (siRNAs), knockdown of pml led to dephosphorylation of TAp73. Knockdown of either pml or TAp73 abolished the imatinib-induced apoptosis. Inhibition of p38 MAPK with SB203580 led to dephosphorylation of TAp73, abolishment of TAp73/PML-NB co-localization, and the subsequent apoptosis. Conversely, interferon alpha-2a (IFNalpha), which increased phosphrylated TAp73 and TAp73/PML-NB co-localization, increased additively apoptosis with imatinib. The imatinib-induced TAp73/PML-NB co-localization was accompanied by co-immpunoprecipitation of TAp73 with pml. The imatinib-induced co-localization was also found in primary CML cells from 3 of 6 patients, including 2 with p53(mutant) and one with p53(wild). A novel p53-independent proapoptotic mechanism using p38 MAPK /pml/TAp73 axis with a step processing at PML-NB and probably with chk2 and bax being involved is hereby evident in some imatinib-treated CML cells.
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PMID:Pml and TAp73 interacting at nuclear body mediate imatinib-induced p53-independent apoptosis of chronic myeloid leukemia cells. 1929 93

In this work we report evidences of a functional relationship between C3G and p38 MAPK in the apoptotic effect of STI-571 on the chronic myeloid leukemia (CML) cell line K562. This has been demonstrated by knocking down C3G and p38alpha using the interfering RNA approach, as well as through targeting p38 by its inhibitor SB203580. The results indicate that p38 is a mediator of the STI-571-induced apoptosis, while C3G plays a negative role on STI-571-mediated p38 activation through a Rap1-dependent mechanism. According to this, gene expression analysis in C3G silenced cells revealed an upregulation of a large number of genes involved in apoptosis. Some of these genes are also down-regulated (at the protein level) upon p38alpha knock-down, which further suggests a functional association between these two proteins. On the other hand, C3G knock-down reverts the STI-571-inhibitory effect on ERKs and Akt pathways in a Rap1-independent fashion. Moreover, C3G overexpression also increased both, basal and STI-571-induced apoptosis, in agreement with previous reports. Therefore, our results strongly suggest a dual regulatory role for C3G in CML cells, modulating both apoptosis and survival via Rap-dependent and independent mechanisms.
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PMID:C3G silencing enhances STI-571-induced apoptosis in CML cells through p38 MAPK activation, but it antagonizes STI-571 inhibitory effect on survival. 1932 82

Dasatinib, a dual Src/Abl tyrosine kinase inhibitor, has significant antileukemic effects against various imatinib mesylate-resistant BCR/ABL mutants. Despite well-documented inhibitory effects of dasatinib on BCR/ABL kinase, the exact downstream cellular events leading to generation of its potent antileukemic effects remain to be defined. We provide evidence that p38 Map kinase (MAPK) pathway is activated leading to increased upregulation of mixed lineage kinase 3, MKK3/6, MSK1, and Mapkapk2, upon treatment of BCR/ABL expressing cells with dasatinib, including cells expressing various imatinib-resistant mutants, except for T315I. Our data demonstrate that such dasatinib-dependent activation of p38 MAPK and its effectors plays a critical role in the generation of antileukemic responses, since pharmacological inhibition of p38 or siRNA-mediated knockdown of its expression reverse dasatinib-mediated apoptosis, cell cycle arrest, and anti-proliferative effects. p38 MAPK inhibition also reversed dasatinib-induced suppression of CML patient-derived leukemic colony-forming units progenitor growth in vitro, as well as BCR/ABL expressing KT-1 cell-derived leukemic progenitor growth. Altogether, our findings suggest a critical role for p38 MAPK pathway in the generation of antileukemic effects of dasatinib, and raise the possibility that development of novel means to enhance p38 MAPK activation in BCR/ABL expressing cells may be an approach to promote antileukemic responses and, possibly, reverse T315I mutation-mediated resistance.
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PMID:Activation of the p38 Map kinase pathway is essential for the antileukemic effects of dasatinib. 2000 Dec 44


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