Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic ductal cancer has higher angiotensin II concentrations compared with normal pancreas or other solid tumors. This study examined angiotensin II type 1 (AT1) receptor expression and the role of angiotensin II in proliferation and survival of human pancreatic cancer cells. All three pancreatic cancer cell lines studied, from well to poorly-differentiated types, HPAF-II, AsPC-1, and Panc-1, showed strong expression of AT1 receptor. In contrast, HT-29 human colon cancer cells showed extremely weak expression. Angiotensin II stimulated the growth of pancreatic cancer cells through MAP kinase activation but had no significant effect on proliferation of HT-29 colon cancer cells. In addition, angiotensin II significantly prevented cisplatin (CDDP)-induced apoptosis through NF-kappaB activation and the subsequent production of anti-apoptotic molecules, including survivin and Bcl-XL, in pancreatic cancer cells. These findings suggest that angiotensin II plays a role in the growth and chemoresistance of AT1-positive pancreatic cancer cells through its action as a potent mitogen and anti-apoptotic molecule.
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PMID:Angiotensin II activates MAP kinase and NF-kappaB through angiotensin II type I receptor in human pancreatic cancer cells. 1537 32

In macrophages, nuclear factor kappa B (NF-kappaB) activation has important roles for the regulation of an inducible nitric oxide synthase (iNOS), several pro-inflammatory cytokines, and anti-apoptotic proteins. In order to analyze the transactivation process of NF-kappaB by lipopolysaccharide (LPS), we used the GAL4-NF-kappaB-p65 fusion protein. This chimeric NF-kappaB is activated transcriptionally only if NF-kappaB transactivation domain is active. With this system, we found that LPS can enhance the transactivation of GAL-NF-kappaB-p65 subunit independent of DNA binding ability and inhibitor of kappaB (IkappaB) regulation. Interestingly, this transactivation by LPS was eliminated with the treatment of U0126, specific inhibitor of mitogen-activated protein kinase (MAPK) kinases (MEKs) 1/2 which has little effect on NF-kappaB activation. We also investigated the effect of inhibitors of apoptosis (IAPs), which might be involved in LPS responses and c-Jun amino terminal kinase (JNKs) activation, on the transactivation of GAL-NF-kappaB-p65. The cIAP1, cIAP2 and XIAP could enhance the NF-kappaB transcription and the chimeric NF-kappaB-p65 transactivation. However, survivin decreased the NF-kappaB transcription and did not influence significantly the chimeric NF-kappaB-p65 transactivation. Taken together, LPS-dependent NF-kappaB transactivation may be involved in extracellular signal-regulated kinase (ERK) pathway and IAPs.
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PMID:Modulation of the transactivation function of nuclear factor-kappaB by lipopolysaccharide in RAW264.7 macrophages. 1537 59

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

Although both the antiapoptotic function of survivin and vitamin D3 (VD3)-mediated cell growth inhibition and apoptosis have been extensively studied, it is not known whether survivin plays a role in VD3 compound-mediated cell growth inhibition and apoptosis induction. Using an isogenic model of MCF-7 breast adenocarcinoma cells (MCF-7E and MCF-7L sublines that are sensitive and resistant to VD3 compounds), we found that VD3 compounds effectively downregulated survivin in VD3-sensitive MCF-7E cells, which was associated with VD3-induced apoptosis. In contrast, VD3 compounds failed to downregulate survivin in VD3-resistant MCF-7L cells, which showed resistant to VD3-induced apoptosis. However, inhibition of survivin expression by small interfering RNA (siRNA) induced cell death per se and further sensitized VD3-induced apoptosis in MCF-7L cells, indicating that the inability of these cells to respond to VD3 is due to the failure to downregulate survivin. Forced expression of survivin not only blocked VD3-mediated G1 cell accumulation but also increased S and G2/M cell populations. VD3 treatment rapidly triggered the activation of p38 MAPK signaling in MCF-7E cells but not in MCF-7L cells. Moreover, inhibition of p38 activation diminished VD3-mediated survivin inhibition and partially rescued VD3-induced cell death. We further showed that VD3 increased the expression of TGF(beta)1 and TGF(beta) receptor 2, and that blocking the function of TGF(beta) receptor 2 diminished VD3 compound-mediated survivin downregulation. Thus, we propose that the VD3 compound-induced growth inhibition and apoptosis induction are at least partially dependent on survivin downregulation via VD3-induced TGFbeta signaling and the activation of p38 MAPK pathway. Targeting survivin through these pathways may lead to novel applications for cancer therapeutics.
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PMID:Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines. 1560 72

We investigated the effect of SCF, a c-kit ligand, on the radiosensitivity of HL60 cells. X-ray-induced apoptosis in HL60 cells was significantly lower in the presence of SCF than in the absence of SCF. This attenuation of X-ray-induced apoptosis by SCF was abolished by PD98059 (an ERK inhibitor), but not by wortmannin (a PI3-K inhibitor) or GF109203X (a PKC inhibitor). The expression of phospho-ERK1/2 (active form) and the ERK1/2-regulated expression of survivin were found to increase in cells treated with X irradiation and SCF. However, X irradiation alone induced down-regulation of the expression of phospho-ERK1/2. Our findings suggest that activation of c-kit by SCF confers radioresistance through up-regulation of ERK-dependent survivin expression in HL60 cells.
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PMID:Activation of c-kit by stem cell factor induces radioresistance to apoptosis through ERK-dependent expression of survivin in HL60 cells. 1563 66

Strategies targeting apoptotic pathways may have relevance to improve the efficacy of antitumor therapy. Because synthetic atypical retinoids are potent inducers of apoptosis, there is an increasing interest in exploiting their potential in novel therapeutic approaches. In the present study, we have investigated the cellular effects of the combination of a novel atypical retinoid, ST1926, and the epidermal growth factor receptor inhibitor ZD1839. The results indicated a synergistic interaction between the two drugs associated with a dramatic enhancement of apoptotic response, up-regulation of the cell death receptor DR5, and caspase 8 activation. Other molecular events induced by the cotreatment included (a) a stabilization of the ST1926-induced genotoxic stress detected by formation of phosphorylated gamma-H2AX foci and (b) a complete inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation associated with activation of the proapoptotic protein BAD (i.e., inhibition of phosphorylation on Ser112). In addition, ZD1839 itself inhibited survival pathways by causing a partial dephosphorylation of Akt and a marked down-regulation of survivin. The role of ERK-mediated survival pathways in the cellular response to the drug combination was further supported by the counteracting effect of stimulation of survival pathways by an alternative receptor tyrosine kinase and by the use of a specific inhibitor of the ERK pathway. In conclusion, the results support that the survival pathways activated by epidermal growth factor receptor are determinants of the cell susceptibility to ST1926-induced apoptosis and lowering survival signals may increase the cellular sensitivity to the atypical retinoid. The favorable pharmacologic profiles of both ST1926 and ZD1839 suggest that the combination of these well-tolerated agents may have therapeutic potential.
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PMID:Modulation of survival signaling pathways and persistence of the genotoxic stress as a basis for the synergistic interaction between the atypical retinoid ST1926 and the epidermal growth factor receptor inhibitor ZD1839. 1578 51

Betulinic acid (BA), a pentacyclic triterpene first identified less than a decade ago, has served as a melanoma-specific cytotoxic agent, and yet its specificity is being challenged. Recently, we found that human melanoma cells exhibited less sensitivity to betulinic acid than human skin keratinocytes. This study was designed to investigate the cell signaling pathway leading human melanoma cells to increased resistance to betulinic acid treatment. In vitro experiments using cultured human melanoma cells indicated that betulinic acid transiently induced survivin expression. The expression of survivin started 30 min post-betulinic acid treatment, peaked at 2 h, remained elevated for 8 h and returned to basal level within 24 h. Similarly, epithelial growth factor (EGF) treatment induced expression of survivin in a time-dependent manner. Since epithelial growth factor receptor (EGFR) activation leads to the activation of cell signaling components that are important to cell survival, we next examined whether BA-induced survivin expression is mediated by the EGFR pathway. The results showed that BA induced EGFR tyrosine phosphorylation in a time-dependent manner. Further, BA strongly induced AKT phosphorylation in a similar pattern. AKT activation started 15 min post-treatment, peaked at approximately 1 h, remained elevated for 4 h and returned to basal level within 8 h. BA also induced ERK activation and, in contrast, weakly induced JNK and p38 activation. Pretreatment of EGFR inhibitor PD153035 blocked BA-induced EGFR phosphorylation, ERK and AKT activation, and survivin expression. Results of the MTT dye assay showed that a combination of PD153035 and BA enhanced melanoma cell death. Collectively, we conclude that betulinic acid transiently activated the EGFR/AKT cell survival pathway and induced survivin expression, contributing to less sensitivity in human melanoma cells. The data suggest that a combination of the EGFR inhibitor and betulinic acid may be a better clinical option to treat human melanoma.
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PMID:Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid. 1607 34

Emerging studies have suggested that transient activation of the cell survival pathway may be the strategy for cancer cells to fight against chemotherapy and eventually mysteriously evade paclitaxel-induced cell death. Modulation of the EGFR-mediated survival pathway in addition to the utilization of paclitaxel renders a promise of better clinical management. The objective of this study was to understand the molecular mechanism of transient induction of EGFR-mediated cell survival by paclitaxel. We utilized ovarian cancer cell line, Caov3, cells to investigate the effect of paclitaxel on EGFR-mediated MAP kinase and AKT activation, and the expression of survivin. We found that paclitaxel transiently induced EGFR phosphorylation and ERK and AKT activation but not JNK and p38. Paclitaxel-induced ERK and AKT activity was inhibited by the EGFR inhibitor, PD153035; ERK inhibitor, U0126; and PI3 kinase inhibitor, LY294002, respectively. We observed that paclitaxel transiently induced expression of survivin in the early hours of treatment. Paclitaxel-induced survivin expression was inhibited by the EGFR inhibitor, PD153035. Inhibitors of EGFR, ERK and PI3 kinase all enhanced paclitaxel-induced cell death. We conclude that paclitaxel transiently transactivates EGFR, leading to activation of cell survival factors, such as ERK and AKT, and expression of survivin, which are all inclusively accountable for ovarian cancer cell resistance to paclitaxel treatment. A combination of these inhibitors with paclitaxel may be a better option for ovarian cancer treatment.
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PMID:Targeted inhibition of transient activation of the EGFR-mediated cell survival pathway enhances paclitaxel-induced ovarian cancer cell death. 1621 Dec 41

KBM5 cells, derived from a patient with blast crisis Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), and imatinib-resistant KBM5 (KBM5-STI571) cells were found to express high levels of survivin. Inhibition of Bcr-Abl by imatinib significantly decreased survivin expression and cell viability in KBM5, but much less so in KBM5-STI571 cells. Inhibition of MEK, downstream of the Bcr-Abl signaling cascade decreased survivin expression and cell viability in both KBM5 and KBM5-STI571 cells. In addition, down-regulation of survivin by a survivin antisense oligonucleotide (Sur-AS-ODN) inhibited cell growth and induced maximal G2M block at 48 hours, whereas cell death was observed only at 72 hours in both KBM5 and KBM5-STI571 cells as shown by annexin V staining. Further, the combination of Sur-AS-ODN and imatinib induced more cell death in KBM5 cells than did either treatment alone. Down-regulating survivin also decreased colony-forming units (CFUs) in blast crisis CML patient samples. Our data therefore suggest that survivin is regulated by the Bcr-Abl/MAPK cascade in Ph+ CML. The facts that down-regulating survivin expression induced cell-growth arrest and subsequent cell death regardless of the cell response to imatinib and enhanced the sensitivity to imatinib suggest the potential therapeutic utility of this strategy in patients with CML, both imatinib sensitive and resistant.
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PMID:Regulation of survivin expression through Bcr-Abl/MAPK cascade: targeting survivin overcomes imatinib resistance and increases imatinib sensitivity in imatinib-responsive CML cells. 1625 45

Survivin is a member of the inhibitors of apoptosis protein (IAP) family and is highly expressed in various cancer cells. However, the molecular mechanisms regulating survivin expression remain unclear. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) in regulating survivin in the human lung adenocarcinoma cell line H1355 in response to arsenic trioxide (As(3+)). Our data indicated that As(3+) induced cytotoxicity accompanied by down-regulation of survivin, cleavage of Poly ADP-ribosyl polymerase (PARP) and activations of MAPKs, including ERK1/2, p38 and c-jun N-terminal kinase (JNK). We found that blockage of p38 or JNK activation attenuated the As(3+)-induced survivin down-regulation and PARP cleavage with significant reversal of cell viability, however, by only 5-8%. On the other hand, the MEK inhibitor PD098059 or the ubiquitin-proteasome inhibitor MG-132 exhibited little effect on survivin down-regulation and PARP cleavage induced by As(3+). In this study, we demonstrated that As(3+) could down-regulate survivin via activations of p38 and JNK in an ubiquitin-proteasome independent pathway and lead to cytotoxicity and apoptosis in the human lung adenocarcinoma cell line H1355.
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PMID:Mitogen-activated protein kinases mediate arsenic-induced down-regulation of survivin in human lung adenocarcinoma cells. 1632 41


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