Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenesis is a critical step in solid tumor progression. The mitogen-activated protein kinase (MAPK) signaling pathways are central to this process, and thus present attractive targets for angiogenesis inhibition. Anthrax Lethal Toxin (LeTx), secreted from the gram positive Bacillus anthracis, demonstrates potent MAPK pathway inhibition. In vivo efficacy studies revealed that LeTx has broad anti-tumor efficacy via the targeting of angiogenesis. However, specificity in animal models was limited due to the presence of receptors on many normal tissues and the ubiquitous expression of furin in tissues. Further, half-life of LeTx was short due to circulating furin-like proteases. Gelatinases are expressed on tumor angiogenic sprouts and only to a limited extent in normal tissues or blood. In order to circumvent nonspecific LeTx activation, enhance tumor vascular targeting, and improve plasma half-life, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. The MMP-activated LeTx showed potent angiogenic inhibition in vivo in the absence of systemic toxicity. Based on these studies, this attenuated toxin has clinical potential as a broad anti-tumor agent.
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PMID:Potent inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin: implications for broad anti-tumor efficacy. 1824 47

Proton beam is useful to target tumor tissue sparing normal cells by allowing precise dose only into tumor cells. However, the cellular and molecular mechanisms by which proton beam induces tumor cell death are still undefined. We irradiated three different tumor cells (LLC, HepG2, and Molt-4) with low energy proton beam (35 MeV) with spread out Bragg peak (SOBP) in vitro, and investigated cell death by MTT or CCK-8 assay at 24 h after irradiation. LLC and HepG2 cells were sensitive to proton beam at over 10 Gy to induce apoptosis whereas Molt-4 showed rather low sensitivity. Relative biological effectiveness (RBE) values for the death rate relative to gamma-ray were ranged from 1.1 to 2.3 in LLC and HepG2 but from 0.3 to 0.7 in Molt-4 at 11 d after irradiation by colony formation assay. The typical apoptotic nuclear DNA morphological pattern was observed by staining with 4'-6-diamidino-2-phenylindole (DAPI). Tiny fragmented DNA was observed in HepG2 but not in Molt-4 by the treatment of proton in apoptotic DNA fragment assay. By FACS analysis after stained with FITC-Annexin-V, early as well as median apoptotic fractions were clearly increased by proton treatment. Proton beam-irradiated tumor cells induced a cleavage of poly (ADP-ribose) polymerase-1 (PARP-1) and procaspases-3 and -9. Activity of caspases was highly enhanced after proton beam irradiation. Reactive oxygen species (ROS) were significantly increased and N-acetyl cysteine pretreatment restored the apoptotic cell death induced by proton beam. Furthermore, p38 and JNK but not ERK were activated by proton and dominant negative mutants of p38 and JNK revived proton-induced apoptosis, suggesting that p38 and JNK pathway may be activated through ROS to activate apoptosis. In conclusion, our data clearly showed that single treatment of low energy proton beam with SOBP increased ROS and induced cell death of solid tumor cells (LLC and HepG2) in an apoptotic cell death program by the induction of caspases activities.
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PMID:Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases. 1830 5

The MUC1 protein is aberrantly expressed on many solid tumor cancers. In contrast to its apical clustering on healthy epithelial cells, it is uniformly distributed over cancer cells. However, a mechanistic link between aberrant expression and cancer has remained elusive. Herein, we report that a membrane-bound MUC1 cleavage product, that we call MUC1*, is the predominant form of the protein on cultured cancer cells and on cancerous tissues. Further, we demonstrate that transfection of a minimal fragment of MUC1, MUC1*(1110), containing a mere forty-five (45) amino acids of the extracellular domain, is sufficient to confer the oncogenic activities that were previously attributed to the full-length protein. By comparison of molecular weight and function, it appears that MUC1* and MUC1*(1110) are approximately equivalent. Evidence is presented that strongly supports a mechanism whereby dimerization of the extracellular domain of MUC1* activates the MAP kinase signaling cascade and stimulates cell growth. These findings suggest methods to manipulate this growth mechanism for therapeutic interventions in cancer treatments.
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PMID:A minimal fragment of MUC1 mediates growth of cancer cells. 1844 42

Arsenic trioxide (As2O3) has been introduced to the treatment of acute promyelocytic leukemia (APL), and has also been shown to induce apoptosis in a variety of solid tumor cell lines, including non-small cell lung cancer. However, the prohibitively high concentration required for the induction of apoptotic cell death in many solid tumor cells is unacceptable for clinical utilization due to the excessive toxicity associated with this dose. Sulindac is known to enhance the cellular responsiveness of tumors toward chemotherapeutic drugs. Herein, we demonstrated that combination treatment with As2O3 and sulindac resulted in a synergistic augmentation of cytotoxicity in H157 lung cancer cells, which was revealed by apoptotic induction as demonstrated by an increase in the sub-G0/G1 fraction. In addition, combination treatment with As2O3 and sulindac increased reactive oxygen species (ROS) and oxidative stress, as evidenced by the heme oxygenase-1 (HO-1) expression and mitogen-activated protein kinase (MAPK) phosphorylation. MAPK inhibitors blocked the induction of HO-1 by combination treatment. Inhibitors of p38 and JNK partially inhibited the augmented cell death whereas the ERK inhibitor showed poor inhibition. Combination treatment with As2O3 and sulindac induced oxidative DNA damage in a time-dependent fashion, which was evaluated by H2AX phosphorylation along with HO-1 induction.
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PMID:Combination treatment with arsenic trioxide and sulindac enhances apoptotic cell death in lung cancer cells via activation of oxidative stress and mitogen-activated protein kinases. 1863 1

TNFalpha activated NF-kappaB and associated regulatory factors including IKK are strongly implicated in a variety of hematological and solid tumor malignancies. We show that tautomycetin (TC) specifically inhibits activation of NF-kappaB among the three TNFalpha effectors (NF-kappaB, JNK and caspase). TC inhibited T-loop phosphorylation of IKKalpha and IKKbeta, thereby preventing degradation of the NF-kappaB inhibitor, IkappaBalpha. Co-immunoprecipitation experiments revealed that the catalytic subunit of PP1 (PP1C) was involved in the IKK complex. Pull-down analysis using recombinant GST-TNFalpha, showed that PP1C was recruited to TNFR1 together with IKK complex, RIP and TAK1 upon stimulus. These results suggest that the PP1 positively regulates the TNFalpha-induced NF-kappaB pathway at the level of IKK activation. Thus, TC might be used therapeutically to suppress the TNFalpha/NF-kappaB pathway.
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PMID:Tautomycetin suppresses the TNFalpha/NF-kappaB pathway via inhibition of IKK activation. 1894 66

SEPT9_v1, the largest transcript of the septin gene family member, SEPT9, encodes a septin isoform implicated in the tumorigenic transformation of mammary epithelial cells. High levels of SEPT9_v1 expression also have been observed in both breast cancer cell lines, primary breast cancers as well as other solid tumor malignancies. We found a novel interaction between SEPT9_v1 and the c-Jun-N-terminal kinase (JNK), a mitogen-activated protein kinase important in cellular stress responses, cell proliferation, and cell survival. We found that up-regulation of SEPT9_v1 stabilizes JNK by delaying its degradation, thereby activating the JNK transcriptome. C-jun kinase assays in mammary epithelial cells expressing SEPT9_v1, compared to controls, exhibited increased JNK/c-Jun transcriptional activity. This increase was associated with increased levels of cyclin D1, a critical component of the proliferative response required for progression through G(1) of the cell cycle in many cell types. These findings demonstrate the first link between a septin protein and the JNK signaling pathway. Importantly, it suggests a novel functional role of SEPT9_v1 in driving cellular proliferation of mammary epithelial cells, a hallmark feature of oncogenesis that is directly relevant to breast cancer.
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PMID:Up-regulation of SEPT9_v1 stabilizes c-Jun-N-terminal kinase and contributes to its pro-proliferative activity in mammary epithelial cells. 1907 Dec 15

Neuroblastoma, the second most common solid tumor in children, frequently metastasizes to the bone marrow and the bone. Neuroblastoma cells present in the bone marrow stimulate the expression of interleukin-6 (IL-6) by bone marrow stromal cells (BMSC) to activate osteoclasts. Here we have examined whether stromal-derived IL-6 also has a paracrine effect on neuroblastoma cells. An analysis of the expression of IL-6 and its receptor, IL-6R, in 11 neuroblastoma cell lines indicated the expression of IL-6 in 4 cell lines and of IL-6R in 9 cell lines. Treatment of IL-6R-positive cells with recombinant human IL-6 resulted in signal transducer and activator of transcription-3 and extracellular signal-regulated kinase-1/2 activation. Culturing IL-6R-positive neuroblastoma cells in the presence of BMSC or recombinant human IL-6 increased proliferation and protected tumor cells from etoposide-induced apoptosis, whereas it had no effect on IL-6R-negative tumor cells. In vivo, neuroblastoma tumors grew faster in the presence of a paracrine source of IL-6. IL-6 induced the expression of cyclooxygenase-2 in neuroblastoma cells with concomitant release of prostaglandin-E2, which increased the expression of IL-6 by BMSC. Supporting a role for stromal-derived IL-6 in patients with neuroblastoma bone metastasis, we observed elevated levels of IL-6 in the serum and bone marrow of 16 patients with neuroblastoma bone metastasis and in BMSC derived from these patients. Altogether, the data indicate that stromal-derived IL-6 contributes to the formation of a bone marrow microenvironment favorable to the progression of metastatic neuroblastoma.
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PMID:Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells. 1911 18

Solid tumor growth is dependent on angiogenesis, the formation of neovasculature from existing vessels. Endothelial activation of the extracellular signal-regulated kinase 1/2, c-jun NH(2)-terminal kinase, and p38 mitogen-activated protein kinase pathways is central to this process, and thus presents an attractive target for the development of angiogenesis inhibitors. Anthrax lethal toxin (LeTx) has potent catalytic mitogen-activated protein kinase inhibition activity. Preclinical studies showed that LeTx induced potent tumor growth inhibition via the inhibition of xenograft vascularization. However, LeTx receptors and the essential furin-like activating proteases are expressed in many normal tissues, potentially limiting the specificity of LeTx as an antitumor agent. To circumvent nonspecific LeTx activation and simultaneously enhance tumor vascular targeting, a substrate preferably cleaved by the gelatinases class of matrix metalloproteinases (MMP) was substituted for the furin LeTx activation site. In vivo efficacy studies showed that this MMP-activated LeTx inhibited tumor xenografts growth via the reduced migration of endothelial cells into the tumor parenchyma. Here we have expanded on these initial findings by showing that this MMP-activated LeTx reduces endothelial proangiogenic MMP expression, thus causing a diminished proteolytic capacity for extracellular matrix remodeling and endothelial differentiation into capillary networks. Additionally, our data suggest that inhibition of the c-jun NH(2)-terminal kinase and p38, but not extracellular signal-regulated kinase-1/2, pathways is significant in the antiangiogenic activity of the MMP-activated LeTx. Collectively, these results support the clinical development of the MMP-activated LeTx for the treatment of solid tumors.
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PMID:Matrix metalloproteinase-activated anthrax lethal toxin inhibits endothelial invasion and neovasculature formation during in vitro morphogenesis. 1937 76

We have previously reported that AD5-10, a novel agonistic monoclonal antibody against DR5, possessed a strong cytotoxic activity in various tumor cells, via induction of caspase-dependent and -independent signaling pathways. The present study further demonstrates that reactive oxygen species (ROS) were generated in abundance in Jurkat leukemia cells upon AD5-10 stimulation and that ROS accumulation subsequently evoked sustained activation of c-Jun N-terminal kinase (JNK), loss of mitochondrial membrane potential, and release of endonuclease G (Endo G) from mitochondria into the cytosol. The reducing agent, N-acetylcysteine (NAC), effectively inhibited the sustained activation of JNK, release of Endo G, and cell death in Jurkat cells treated by AD5-10. Moreover, a dominant-negative form of JNK (but not of p38) enhanced NF-kappaB activation, suppressed caspase-8 recruitment in death-inducing signaling complexes (DISCs), and reduced adverse effects on mitochondria, thereby inhibiting AD5-10-induced cell death in Jurkat leukemia cells. These data provide novel information on the DR5-mediated cell death-signaling pathway and may shed new light on effective strategies for leukemia and solid tumor therapies.
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PMID:An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells. 1946 86

Eukaryotic translation initiation factor 4E (eIF4E) is a rate-limiting factor for cap-dependent protein synthesis and is regulated by PI3 kinase/mTOR and mitogen-activated protein kinase (MAPK)/Mnk signaling pathways. Recent studies have shown that Mnk-mediated eIF4E phosphorylation is absolutely required for eIF4E's oncogenic function. Overexpression of eIF4E has been reported in many types of cancers; however, the expression of phosphorylated eIF4E (p-eIF4E) in human cancer tissues, particularly solid tumor tissues, has not been reported. The current study focused on evaluating p-eIF4E expression patterns in the tumor tissues obtained from patients with a variety of malignancies. Using three different tissue microarrays consisting of a total of 380 cases of human cancers and 146 cases of adjacent normal tissues, we detected p-eIF4E positive staining in 63.4% (241/380) of cancers, but only in 30.1% (44/146) of adjacent normal tissues. Thus, p-eIF4E expression is significantly higher in cancers than in adjacent normal tissues (p < 0.001). In general, there was no major difference in p-eIF4E staining between cancers with and without lymph node metastasis. In certain types of maligancies such as lung, gastric and colorectal cancers, p-eIF4E staining was significantly higher in the early stage (T1) than in the late stage (T3) disease (p < 0.05). Collectively, these findings suggest that p-eIF4E may play a critical role in cancer development, particularly early stages of tumorigenesis and support p-eIF4E as a good cancer therapeutic target.
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PMID:Phosphorylated eukaryotic translation initiation factor 4 (eIF4E) is elevated in human cancer tissues. 1948 68


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