Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone-related protein (PTHrP), a paraneoplastic protein expressed by two-thirds of human non-small cell lung cancers, has been reported to slow progression of lung carcinomas in mouse models and to lengthen survival of patients with lung cancer. This study investigated the effects of ectopic expression of PTHrP on proliferation and cell cycle progression of two human lung adenocarcinoma cell lines that are normally PTHrP negative. Stable transfection with PTHrP decreased H1944 cell DNA synthesis, measured by thymidine incorporation, bromodeoxyuridine uptake, and MTT proliferation assay. A substantial fraction of PTHrP-positive cells was arrested in or slowly progressing through G1. Cyclin D2 and cyclin A2 protein levels were 60-70% lower in PTHrP-expressing cells compared with control cells (P < 0.05, N = 3 independent clones per group), while expression of p27(Kip1), a cyclin-dependent kinase inhibitor, was increased by 35 +/- 9% (mean +/- SE, P < 0.05) in the presence of PTHrP. Expression of other cyclins, including cyclins D1 and D3, and cyclin-dependent kinases was unaffected by PTHrP. PTHrP did not alter the phosphorylation state of Rb, but decreased cyclin-dependent kinase (CDK) 2-cyclin A2 complex formation. Ectopic expression of PTHrP stimulated ERK phosphorylation. In MV522 cells, PTHrP had similar effects on DNA synthesis, cyclin A2 expression, pRb levels, CDK2-cyclin A2 association, and ERK activation. In summary, PTHrP appears to slow progression of lung cancer cells into S phase, possibly by decreasing activation of CDK2. Slower cancer cell proliferation could contribute to slower tumor progression and increased survival of patients with PTHrP-positive lung cancer.
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PMID:Cell cycle actions of parathyroid hormone-related protein in non-small cell lung carcinoma. 1963 68

The effect of epigallocatechin gallate (EGCG) on cell survival was studied by using serum-starved A549 non-small cell lung carcinoma (NSCLC) cells. A MTT assay showed that EGCG significantly increased the viability of serum-starved A549 cells compared to the control cells, though EGCG at high concentration (approximately 300 microM) had no protective effect against serum withdrawal-induced cell apoptosis. Western blots showed increased immunoreactivity for phospho-Akt and phospho-GSK3beta in EGCG-treated cells. To determine the mechanism for Akt phosphorylation, cells were pretreated with various kinase inhibitors before exposure to EGCG. Only LY294002 inhibited Akt activation induced by EGCG, implying that EGCG-induced Akt activation is PI3K dependent. Both phospho-Raf-1 and Raf-1 proteins were significantly decreased, whereas B-raf expression was not altered. This suggests that the Raf kinases have no role in the increased cell survival caused by EGCG. This study has shown that EGCG protects A549 cells from apoptosis induced by serum deprivation via Akt activation and this protective effect may limit the clinical use of EGCG in treating and preventing NSCLC.
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PMID:(-)-Epigallocatechin-3-gallate (EGCG) increases the viability of serum-starved A549 cells through its effect on Akt. 1965 10

The aim of this study is to clarify the benefit of combination chemotherapy in gastric cancer based on a cell-signal inhibitor and an anticancer drug. Two scirrhous gastric cancer cell lines and two non-scirrhous gastric cancer cell lines were used. Five anticancer drugs (5-fluorouracil [5FU], paclitaxel, oxaliplatin, irinotecan, and gemcitabine) and four cell-signal inhibitors, mammalian target of rapamycin (mTOR) inhibitor, glycogen synthase kinase 3beta, p38alphabetaMAPK, and cyclin-dependent kinase, were used. The proliferation of cancer cells was examined by MTT assay and in vivo study. The apoptosis of cancer cells and the expression of apoptosis-related molecules were examined by flow cytometry, real-time PCR, and immunostaining. mTOR inhibitors with 5FU showed a synergistic antiproliferative effect in scirrhous gastric cancer, whereas the other signal inhibitors showed no synergistic effect with any anticancer drugs. mTOR inhibitor decreased the IC(50) of 5FU and increased the apoptosis rate in scirrhous gastric cancer cells, but not in non-scirrhous gastric cancer cells. The pan-caspase inhibitor, zVAD-fmk, inhibits apoptosis induced in combination with 5FU and mTOR inhibitor. mTOR inhibitor decreased dihydropyrimidine dehydrogenase, thymidylatesynthase, and bcl-2 expression, and increased caspase-3 and p21 expression of scirrhous gastric cancer cells, but did not affect those of non-scirrhous gastric cancer cells. In an in vivo study, mTOR inhibitor significantly enhanced the therapeutic efficacy of S1, an analog of 5FU. These findings suggest that mTOR inhibitor interacts with 5FU in a synergistic manner in scirrhous gastric cancer cells by the activation of the apoptosis signal. Therefore, mTOR inhibitor is a promising therapeutic agent in combination with 5FU in scirrhous gastric cancer.
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PMID:Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer. 1976 96

Salidroside is isolated from Rhodiola rosea L., a traditional Chinese medicinal plant, and has a potent antioxidant property. The aim of this study was to investigate the effects of salidroside on hydrogen peroxide (H(2)O(2))-induced cell apoptosis in nerve growth factor (NGF)-differentiated PC12 cells and the possible involvement of the extracellular signal-related protein kinase 1/2 (ERK1/2) signaling pathway. MTT assay, Hoechst 33342 staining, and TdT-mediated dUTP-biotin nick end labeling assay collectively showed that pretreatment with salidroside alleviated, in a dose-dependent manner, cell viability loss and apoptotic cell death induced by H(2)O(2) stimulation in cultured NGF-differentiated PC12 cells. According to Western blot analysis, pretreatment with salidroside transiently caused the activation of ERK1/2 pathway; a selective inhibitor of the mitogen-activated protein kinase kinase (MAPKK, MEK) blocked salidroside-activated ERK pathway and thus attenuated the influences of salidroside on H(2)O(2)-induced increase in the level of cleaved caspase-3, a chief executant of apoptosis cascades. Morphological analysis further indicated that in the presence of the MEK inhibitor, the neuroprotective effect of salidroside against H(2)O(2)-evoked cell apoptosis was significantly abrogated. Taken together, the results suggest that the neuroprotective effects of salidroside might be modulated by ERK signaling pathway, especially at the level or upstream of the caspase-3 activation.
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PMID:Involvement of ERK1/2 pathway in neuroprotection by salidroside against hydrogen peroxide-induced apoptotic cell death. 1978 59

Rotenone, a mitochondrial complex I inhibitor, can induce the pathological features of Parkinson's disease (PD). In the present study, naringin, a grapefruit flavonoid, inhibited rotenone-induced cell death in human neuroblastoma SH-SY5Y cells. We assessed cell death and apoptosis by measuring mitogen-activated protein kinase (MAPKs) and caspase (CASPs) activities and by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 4,6-diamidino-2-phenylindole (DAPI) staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Naringin also blocked rotenone-induced phosphorylation of Jun NH2-terminal protein kinase (JNK) and P38, and prevented changes in B-cell CLL/lymphoma 2 (BCL2) and BCL2-associated X protein (BAX) expression levels. In addition, naringin reduced the enzyme activity of caspase 3 and cleavages of caspase 9, poly (ADP-ribose) polymerase (PARP), and caspase 3. These results suggest that naringin has a neuroprotective effect on rotenone-induced cell death in human neuroblastoma SH-SY5Y cells.
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PMID:Naringin Protects against Rotenone-induced Apoptosis in Human Neuroblastoma SH-SY5Y Cells. 1988 11

Ischemia/hypoxia is known to induce the neural stem cells proliferation and neural differentiation in rodent and human brain; however its mechanisms remain largely unknown. In this study we investigated the effect of hypoxia on neural stem cells (NSCs) proliferation with the expression of cyclin D1 and the phosphorylation of mitogen-activated protein kinases (MAPK) signaling molecules. NSCs were cultured from cortex of fetal Sprague-Dawley rats on embryonic day 5.5. The hypoxia was made using a microaerophilic incubation system. The NSCs proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, diameter measurement of neurospheres, bromodeoxyuridine (BrdU) incorporation assay and cell cycle analysis. The cell death of NSCs was evaluated by terminal dUTP nick-end labeling (TUNEL) assay. The expression of cyclin D1, phosphorylated extracellular signal regulated kinase (ERK), c-Jun N-terminal protein kinase (JNK) and p38 were analyzed by immunoblotting assay. The results showed that hypoxia increased NSCs proliferation in cell amount, diameter of neurospheres, BrdU incorporation and cell division, and the highest proliferation of the NSCs was observed with 12 h hypoxic treatment; hypoxia did not decrease cell death of NSCs; after hypoxic treatment, the expression of cyclin D1 increased, meanwhile P-JNK2 level increased, P-p38 decreased, and no significant change in P-ERK2 level compared to normoxic cultures. JNK inhibitor SP600125 attenuated the increase of cyclin D1 induced by hypoxia. These findings propose that hypoxia increases cyclin D1 expression through activation of JNK in NSCs of rat in vitro, suggesting a novel possible mechanism for hypoxia-induced proliferation of NSCs.
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PMID:Hypoxia stimulates proliferation of rat neural stem cells with influence on the expression of cyclin D1 and c-Jun N-terminal protein kinase signaling pathway in vitro. 1990 92

Calcium-calmodulin-dependent protein kinase II (CaMKII) is one of the main protein kinases mediating intracellular Ca changes. It is also involved in the process of cardiac diseases, such as cardiac hypertrophy, but its effects on myocardial fibrosis remain unclear. The present study investigates whether CaMKII is involved in cardiac fibroblast proliferation and extracellular matrix (ECM) secretion induced by angiotensin II (AngII) or electrical field stimulation (EFS) in cultured neonatal rat cardiac fibroblasts. Cardiac fibroblast proliferation was assessed by a cell survival assay (MTT) and manual cell enumeration. Cellular matrix production was demonstrated by matrix metalloproteinases (MMP) 1, 2, 9, and collagen I/III messenger RNA expression, MMP-2, 9 protein expression, and secretion of transforming growth factor beta1 and tumor necrosis factor alpha. Either AngII or EFS promoted cardiac fibroblast proliferation and ECM secretion, while also up-regulating expression of CaMKII deltaB and deltaC. More importantly, CaMKII inhibitors, autocamtide-2-related inhibitory peptide (AIP 5 microM) or KN93 (0.5 microM), suppressed cardiac fibroblast proliferation, inhibited the excretion of transforming growth factor beta1 and tumor necrosis factor alpha, decreased the messenger RNA expression of MMP-1, 2, 9 and collagen I/III, and decreased the protein expression of MMP-2, 9. These results suggest that CaMKII mediates cardiac fibroblast proliferation and ECM secretion induced by either AngII or EFS.
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PMID:Inhibition of calcium-calmodulin-dependent kinase II suppresses cardiac fibroblast proliferation and extracellular matrix secretion. 1993 79

In some human cancers, the Notch1 receptor and signaling pathway is upregulated, which increases the oncogenic potential of the cell through prevention of differentiation and inhibition of apoptosis. We sought to evaluate the role of Notch1 in hepatocellular cancer (HCC), and evaluate the therapeutic efficacy of curcumin, a known Notch1 inhibitor. Human liver tumors were compared to normal liver to evaluate for Notch1 and Notch1 Intracellular Domain (NICD). Three human HCC cell lines were exposed to curcumin and evaluated for downstream effectors by Western blot. In addition, standard MTT assays were performed to assess the effect of curcumin in vitro. Finally, a nude mouse xenograft model was utilized to assess the response to curcumin in vivo. High levels of NICD were present in the majority of human HCC samples and all three HCC cell lines. Treatment with curcumin led to a dose-dependent decrease in the expression of NICD associated with the induction of cleaved poly ADP-ribose polymerase (PARP), the degradation of cyclin D1 and increase in cyclin-dependent kinase p21. Curcumin inhibited HCC cell proliferation in vitro. Importantly, transfection of Notch1 small-interfering RNA (siRNA) into HCC cells resulted in cell growth inhibition and apoptosis, recapitulating the effects of curcumin. Finally, treatment with curcumin resulted in a 40% decrease in tumor growth in vivo. These results suggest for the first time that down-regulation of Notch1 signaling with curcumin is an attractive new therapeutic strategy for the treatment of patients with HCC.
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PMID:Down-regulation of Notch1 signaling inhibits tumor growth in human hepatocellular carcinoma. 1995 48

Curcumin has been shown to induce apoptosis in various malignant cancer cell lines. One mechanism of curcumin-induced apoptosis is through the PI3K/Akt signaling pathway. Akt, also known as protein kinase B (PKB), is a member of the family of phosphatidylinositol 3-OH-kinase regulated Ser/Thr kinases. The active Akt regulates cell survival and proliferation; and inhibits apoptosis. In this study we found that curcumin induces apoptotic cell death in MCF-7 cells, as assessed by MTT assay, DNA ladder formation, PARP cleavage, p53 and Bax induction. At apoptotic inducing concentration, curcumin induces a dramatic Akt phosphorylation, accompanied by an increased phosphorylation of glycogen synthase kinase 3beta (GSK3beta), which has been considered to be a pro-growth signaling molecule. Combining curcumin with PI3K inhibitor, LY290042, synergizes the apoptotic effect of curcumin. The inhibitor LY290042 was capable of attenuating curcumin-induced Akt phosphorylation and activation of GSK3beta. All together, our data suggest that blocking the PI3K/Akt survival pathway sensitizes the curcumin-induced apoptosis in MCF-7 cells.
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PMID:Modulation of curcumin-induced Akt phosphorylation and apoptosis by PI3K inhibitor in MCF-7 cells. 2013 29

Several studies indicate the involvement of protein kinases in the progression of various malignancies. Kinase inhibitors are therefore becoming important anticancer drugs. CK2 kinase (casein kinase-2) has been suggested to be a constituent of a neoplastic milleu, and its inhibition might represent a new approach to cancer therapy. Adrenocortical carcinomas (ACCs) are highly malignant neoplasms with poor overall prognosis. We have examined the effects of 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), a potent CK2 inhibitor, on the H295R human adrenocortical cancer cell line. Treatment with DMAT decreases the secretion of aldosterone, dehydroepiandrosterone sulfate, and androstendione and results in an accumulation of 17-OH-progesterone. Cell growth as measured by the MTT and 5-bromo-2'-deoxyuridine incorporation assays is inhibited, and cell cycle analysis has revealed a slight induction of apoptosis. Thus, CK2 kinase activity is probably involved in human ACC endocrine activity and growth.
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PMID:Anti-neoplastic effect of protein kinase CK2 inhibitor, 2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT), on growth and hormonal activity of human adrenocortical carcinoma cell line (H295R) in vitro. 2038 46


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