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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of <5%. Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is highly resistant to conventional chemotherapies, underscoring the critical need for new molecular targets for pancreatic cancer chemotherapy. The KRAS proto-oncogene is mutated in >90% of PDAC. Protein kinase Ciota (PKCiota) is required for the oncogenic Ras-mediated transformed growth of lung cancer and intestinal epithelial cells. However, little is known about the role of PKCiota in pancreatic cancer. In this study, we evaluated the expression of PKCiota in human pancreatic cancer and the requirement for PKCiota for the transformed growth and tumorigenicity of PDAC cells. We find that PKCiota is significantly overexpressed in human pancreatic cancer, and high PKCiota expression correlates with poor patient survival. Inhibition of PKCiota expression blocks PDAC cell transformed growth in vitro and tumorigenicity in vivo. Inhibition of PKCiota expression in pancreatic tumors also significantly reduces tumor angiogenesis and metastasis. Analysis of downstream PKCiota effectors implicates the Rac1-MEK/ERK1/2 signaling axis in PKCiota-mediated transformed growth and cellular invasion. Taken together, our data show a required role for PKCiota in the transformed growth of pancreatic cancer cells and reveal a novel role for PKCiota in pancreatic cancer cell metastasis and angiogenesis in vivo. Our results strongly indicate that PKCiota will be an effective target for pancreatic cancer therapy.
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PMID:Protein kinase Ciota is required for pancreatic cancer cell transformed growth and tumorigenesis. 2017 10

Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a contagious lung cancer in sheep that shares similarities with human bronchioloalveolar carcinoma (BAC). JSRV is unique because the envelope gene (env) is the oncogene, as it can transform cells in culture and induce tumors in animals. The phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR and H/N-Ras-MEK-mitogen-activated protein kinase (MAPK) pathways have been shown to be critical for Env transformation. However, the question still remains of how disruption of these pathways relates to tumor formation. To address this, JSRV Env transformation was studied in the context of epithelial structure, using the polarized Madin-Darby canine kidney (MDCK) epithelial cell three-dimensional (3-D) culture system. The results indicated that JSRV Env-transformed MDCK cells were larger and had full or multiple lumens, in contrast to the single lumens observed in controls. The altered phenotype was largely mediated by an increase in proliferation, in addition to overcoming the proliferative suppression signal. JSRV Env was not found to disrupt polarity or tight junctions or to inhibit lumen apoptosis. The PI3K-Akt-mTOR pathway was important for Env transformation in MDCK cells, although the mechanisms of action differed in 3-D and monolayer cultures. PI3K-dependent signaling to mTOR occurred in monolayers, while PI3K-independent signaling to mTOR occurred in 3-D culture. In contrast, the H/N-Ras-MEK-MAPK pathway was found to be inhibitory to transformation in both normal and transformed MDCK cells in 3-D culture. However, in monolayer culture, inhibition of MEK reverted the transformed phenotype, suggesting a different mechanism(s) of action in monolayer versus 3-D culture.
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PMID:Jaagsiekte sheep retrovirus transformation in Madin-Darby canine kidney epithelial cell three-dimensional culture. 2021 22

MG132, as a proteasome inhibitor, can induce apoptotic cell death through formation of reactive oxygen species (ROS). In this study, we investigated the effects of MAPK (MEK, JNK, and p38) inhibitors on MG132-treated A549 lung cancer cells in relation to cell growth, cell death, ROS, and glutathione (GSH) levels. Treatment with 10 microM MG132 inhibited the growth of A549 cells at 24 h. MG132 also induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; deltapsi(m)). ROS were not increased in MG132-treated A549 cells. MG132 increased GSH-depleted cell numbers and decreased GSH levels. MEK and JNK inhibitors did not strongly affect cell growth, cell death, ROS, and GSH levels in MG132-treated A549 cells. In contrast, p38 inhibitor reduced cell growth inhibition, apoptosis, and MMP (deltapsi(m)) loss by MG132. However, p38 inhibitor did not change ROS level and GSH content. In conclusion, MG132 inhibited the growth of A549 cells via apoptosis without formation of ROS. Treatment with p38 inhibitor rescued some cells from MG132-induced apotposis, which was not affected by ROS and GSH level changes.
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PMID:The attenuation of MG132, a proteasome inhibitor, induced A549 lung cancer cell death by p38 inhibitor in ROS-independent manner. 2037 32

Anthocyanins, present in various vegetables and fruits as a nature colorant, have broad activities including anticarcinogenesis and antimutagenesis, which are generally attributed to their antioxidant activities. However, limited studies have been available concerning the inhibitory effect of peonidin 3-glucoside (P3G) for cancer metastasis. Here, we demonstrated that P3G could significantly inhibit the invasion (P < 0.001), motility (P < 0.05), secretion of matrix metalloproteinase (MMP)-2, MMP-9, and urokinase-type plasminogen activator (u-PA) of lung cancer cells. Meanwhile, P3G attenuated phosphorylation of extracellular signal-regulated kinase (ERK)1/2, a member of mitogen-activated protein kinase (MAPK) family involved in the upregulation of MMPs and u-PA, and also inhibited the activation of activating protein-1 (AP-1) as shown by Western blot and electrophoretic mobility shift assay. Thus, the inhibitory effects of P3G may be at least partly through inactivation of ERK 1/2 and AP-1 signaling pathways as confirmed by abolishment of P3G-inhibited H1299 cell invasion by overexpression of MAPK kinase 1 (MEK1). Finally, P3G was evidenced by its inhibition on the metastasis of Lewis lung carcinoma cells in vivo (P < 0.001). Taken together, these findings suggested that P3G could reduce the metastasis of lung cancer cells, thereby constituting an adjuvant treatment for metastasis control.
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PMID:Peonidin 3-glucoside inhibits lung cancer metastasis by downregulation of proteinases activities and MAPK pathway. 2043 72

MG132 (carbobenzoxy-Leu-Leu-leucinal) as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). In this study, we investigated the effects of MEK (mitogen-activated protein [MAP] kinase or extracellular signal-regulated kinase [ERK] kinase) or p38 inhibitor on MG132-treated Calu-6 lung cancer cells in relation to cell growth, cell death, ROS, and glutathione (GSH) levels. Treatment with 10 mumol/L MG132 inhibited the growth of Calu-6 cells at 24 hours. MG132 induced apoptosis in Calu-6 cells, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). ROS were increased in MG132-treated Calu-6 cells. MG132 also induced GSH depletion in Calu-6 cells. Treatment with MEK inhibitor did not significantly affect cell growth, cell death, ROS, and GSH levels in MG132-treated Calu-6 cells. Furthermore, MG132 increased the phosphorylation of p38 in Calu-6 cells at 1 and 24 hours. Treatment with p38 inhibitor significantly prevented cell growth inhibition, MMP (DeltaPsi(m)) loss and apoptosis in MG132-treated Calu-6 cells. This inhibitor increased ROS level and decreased GSH depletion in these cells. In conclusion, p38 inhibitor partially prevented Calu-6 cell death by MG132, which might be affected by GSH level changes.
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PMID:Treatment with p38 inhibitor partially prevents Calu-6 lung cancer cell death by a proteasome inhibitor, MG132. 2047 10

Treatment outcomes in advanced or metastatic non-small-cell lung cancer (NSCLC) remain unsatisfactory, with low long-term survival rates. Palliative chemotherapy offers a median survival not exceeding 1 year. To date, various combinations of cytotoxic drugs have not improved treatment results beyond what has been observed with platinum doublets. By contrast, molecular targeted drugs may block important pathways that drive cancer progression and achieve long-term disease control. Conflicting results have demonstrated marginal benefit with EGFR inhibitors, anti-EGFR monoclonal antibodies and antiangiogenic strategies in unselected populations of patients with advanced NSCLC. However, patients with an EGFR mutation are likely to respond to agents that target this gene. Novel targeted therapies that interfere with insulin-like growth factor 1 receptor, or the EML4-ALK fusion protein have shown promising activity. Aberrations in other key signaling pathways and molecules, such as RAS/RAF/MEK, PI3K/AKT/mTOR, or MET kinase, have been identified as crucial targets, especially in resistant patients. Novel drugs aimed at these abnormalities are already in the clinic. This Review outlines the current state-of-the-art research for targeted therapy in NSCLC.
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PMID:Targeted therapy in non-small-cell lung cancer--is it becoming a reality? 2055 45

It is now clear that the association between cancer cells and recruited fibroblasts (cancer-associated fibroblasts; CAFs) leads to alteration of the biological properties of both types of cells and creates a specific microenvironment. Here we report a novel biological property of CAFs and its cellular mechanism using in vivo and in vitro model. Cultured CAFs derived from human lung cancer tissue displayed significantly higher migration activity in response to PDGF-BB than that of fibroblasts from corresponding non-cancerous tissue (NCAFs). Moreover, KM104GFP (GFP-labeled human fibroblast cell line) co-cultured with human cancer cell line Capan-1 showed significantly higher migration activity than KM104GFP alone. No such phenomenon occurred when KM104GFP and Capan-1 were cultured separately. Even after KM104GFP were sorted from co-cultured Capan-1, KM104GFP retained their enhanced migration activity until passage-5 of culture in the absence of cancer cells. Despite a similar level of phosphorylation of ERK1/2 after exposure to PDGF-BB, the inhibitory effect of MEK inhibitor was significantly higher on migration of KM104GFP that had been sorted from co-cultured Capan-1 than of KM104GFP alone. This higher dependence on ERK1/2 signaling for cell migration was also seen in CAFs obtained from cancer tissue. The results of this study indicate that by association with cancer cells, CAFs can acquire enhanced migration activity which could be kept after separation from cancer cells and suggest the possibility that higher dependence on ERK1/2 signaling for enhanced migration activity would be one of the biological properties of CAFs.
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PMID:Fibroblasts associated with cancer cells keep enhanced migration activity after separation from cancer cells: a novel character of tumor educated fibroblasts. 2059 59

Lung cancer is the leading cause of cancer-related deaths in the world, and non-small-cell lung cancer (NSCLC) accounts for 80% of cases. MicroRNA-21 (miR-21) expression is increased and predicts poor survival in NSCLC. Although miR-21 function has been studied in vitro with cancer cell lines, the role of miR-21 in tumor development in vivo is unknown. We utilize transgenic mice with loss-of-function and gain-of-function miR-21 alleles combined with a model of NSCLC to determine the role of miR-21 in lung cancer. We show that overexpression of miR-21 enhances tumorigenesis and that genetic deletion of miR-21 partially protects against tumor formation. MiR-21 drives tumorigenesis through inhibition of negative regulators of the Ras/MEK/ERK pathway and inhibition of apoptosis.
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PMID:Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. 2083 48

NSC-741909 (1-[(4-chlorophenyl)methyl]-1H-Indole-3-methanol) is a novel anticancer agent that is highly active against several NCI-60 cancer cell lines. This agent induces sustained activation of mitogen-activated protein kinases (MAPK), including JNK and p38 MAP kinases. However, the mechanisms of its selective antitumor activity in some cancer cell lines remain unknown. We tested the combined effects of NSC-741909 and several kinase inhibitors that target the Raf/MEK/ERK1/2 or PI3K/AKT pathways in two sensitive lung cancer cells. We found that PD98059 (2'-amino-3'-methoxyflavone), a flavone derivative and a selective MEK inhibitor, can dramatically block the cell killing effect of NSC-741909. To determine whether this inhibitory effect is associated with MEK inhibition or other mechanisms, we evaluated the effects of other MEK inhibitors with different chemical structures and flavone derivatives that do not have an effect on MEK. We found that several flavonoids can markedly block NSC-741909-induced apoptosis and JNK activation in a time-dependent manner, regardless of whether they inhibit MEK or not. In contrast, NSC-741909-induced JNK activation and apoptosis were not blocked by other MEK-specific inhibitors U0126 and CI1040. Our results also showed that NSC-741909 induced a dramatic increase of reactive oxygen species in sensitive cells and that flavonoids effectively blocked the NSC-741909-induced reactive oxygen species production which are associated with flavonoids' antagonistic effects on NSC-741909-induced JNK activation and apoptosis. Those results demonstrated that flavonoids-mediated antagonist effect is through scavenging of reactive oxygen species. Our results may have implication on the design of clinical evaluation of antitumor activity of NSC-741909 or its analogues.
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PMID:Antagonistic effect of flavonoids on NSC-741909-mediated antitumor activity via scavenging of reactive oxygen species. 2085 5

Gemcitabine (2',2'-difluorodeoxycytidine), a deoxycytidine analog, and erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, are used clinically to treat patients with non-small-cell lung cancer (NSCLC). However, the molecular mechanisms for the drug resistance of gemcitabine in NSCLC cells are poorly understood. In this study, we used constructs containing human Rad51 cDNA or specific Rad51 small interfering RNA (siRNA) to examine the role of Rad51 in chemoresistance of gemcitabine in three different human NSCLC cell lines. Exposure of human NSCLC cell lines to gemcitabine increased the phosphorylation levels of mitogen-activated protein kinase kinase (MKK) 1/2-extracellular signal-regulated kinase (ERK) 1/2 and AKT in a time- and dose-dependent manner, which was accompanied by an induction of Rad51 mRNA and protein expression. Gemcitabine increased the expression of Rad51 by increasing its mRNA and protein stability. Blockage of ERK1/2 or AKT activation by 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126; MKK1/2 inhibitor) or 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002; phosphatidyl inositol 3-kinase inhibitor), respectively, decreased the gemcitabine-induced Rad51 expression. Gemcitabine-induced cytotoxicity was significantly increased using siRNA depletion of Rad51 or blockage of ERK1/2 and AKT activation. Erlotinib enhanced the gemcitabine-induced cytotoxicity via the inactivation of ERK1/2 and AKT and the down-regulation of Rad51. Enforced expression of constitutively active MKK1/2 or AKT recovered cell viability and Rad51 protein levels that were decreased by the combination of erlotinib and gemcitabine. Suppression of Rad51 expression or the inactivation of ERK1/2 or AKT signaling may be considered potential therapeutic modalities for gemcitabine-resistant lung cancer.
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PMID:Down-regulation of Rad51 expression overcomes drug resistance to gemcitabine in human non-small-cell lung cancer cells. 2085 43


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