Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysregulation of hepatocyte growth factor (HGF)-induced signaling via its receptor tyrosine kinase Met results in tumor progression and metastasis. To initiate signaling, pro-HGF must be proteolytically activated to reveal a secondary Met binding site within the serine protease-like beta-chain of HGF. Although HGF/Met is a large complex, we sought to discover relatively small antagonists that might interfere with this critical Met binding region. Pools of disulfide-constrained random peptide libraries displayed on phage were selected for binding to HGF, ultimately resulting in a disulfide-constrained 15-mer peptide (VNWVCFRDVGCDWVL) termed HB10, which bound to the recombinant human HGF beta-chain (HGF beta) and competitively inhibited binding to Met with an IC(50) of 450 nM. In MDA-MB435 cells, HB10 reduced HGF-dependent Met phosphorylation by 70%, and phosphorylation of downstream kinases AKT and ERK1/ERK2 by 74% and 69%, respectively. Addition of HB10 also inhibited HGF-dependent migration of these cells with an IC(50) of approximately 20 microM. The 2D (1)H-NMR structure of HB10 revealed a beta-hairpin loop stabilized by the disulfide bond and cross-strand pairing of Trp3 and Trp13. HGF beta mutants deficient in Met binding also have reduced HB10 binding, suggesting an overlapping binding site. Notably HB10 did not inhibit full length HGF binding to Met. Thus steric hindrance of the interaction between HGF beta domain binding to Met is sufficient for inhibiting full-length HGF-dependent Met signaling and cell migration that is consistent with a noncompetitive inhibitory mechanism of Met signal transduction.
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PMID:Noncompetitive inhibition of hepatocyte growth factor-dependent Met signaling by a phage-derived peptide. 1897 60

The recruitment of leukocytes to injured tissue is crucial for the initiation of inflammatory responses as well as for immune surveillance to fight tumor progression. In this study, we show that oncostatin M, a member of the IL-6-type cytokine family and potent proinflammatory cytokine stimulates the expression of the chemokines CCL1, CCL7, and CCL8 in primary human dermal fibroblasts at a faster kinetic than IL-1beta or TNF-alpha. The production of CCL1 and CCL8 is important for migration of monocytes, while specific Abs against CCL1 additionally inhibit the migration of T lymphocytes. We identify the mitogen-activated protein kinases ERK1/2 and p38 as crucial factors for the enhanced expression of CCL1 and CCL8. Depletion of the ERK1/2 target genes c-Jun or c-Fos strongly decrease CCL1 and CCL8 expression, while p38 MAPK prolongs the half-life of CCL1, CCL7, and CCL8 mRNA through inhibition of tristetraprolin. None of the STAT transcription factors STAT1, STAT3, or STAT5 stimulate transcription of CCL1 or CCL8. However, we identify a negative regulatory function of activated STAT5 for the gene expression of CCL1. Importantly, not STAT5 itself, but its target gene cytokine inducible SH2-domain containing protein is required for the STAT5 inhibitory effect on CCL1 expression. Finally, we show that constitutive activation of STAT5 through a mutated form of JAK2 (JAK2 V617F) occurring in patients with myeloproliferative disorders similarly suppresses CCL1 expression. Taken together, we identify novel important inflammatory target genes of OSM which are independent of STAT signaling per se, but depend on MAPK activation and are partly repressed through STAT5-dependent expression of cytokine inducible SH2-domain containing protein.
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PMID:Oncostatin M-induced and constitutive activation of the JAK2/STAT5/CIS pathway suppresses CCL1, but not CCL7 and CCL8, chemokine expression. 1898 Nov 57

Lung metastasis is one of the important characteristics of salivary adenoid cystic carcinoma (SACC). Although activation of extracellular signal-regulated kinase 1/2 (ERK1/2) pathway may be associated with cancer progression in some malignant tumors, its roles in lung metastasis of SACC remains unclear. We examined the expression of activated ERK1/2 in SACC-LM with high lung-metastatic rate and SACC-83 with low lung-metastatic rate, as well as in the tissues from lung-metastatic and non-metastatic groups of SACC patients. Western blot analysis indicated that SACC-LM exhibited higher expression of activated ERK1/2 than SACC-83. Similarly, immunohistochemistry showed that expression of activated ERK1/2 was detected in 73% (8/11) of the primary tissues from SACC patients with lung metastasis, while only 25% (3/12) of the primary tissues from SACC patients without lung metastasis (P<0.05). Furthermore, we examined the effects of U0126, a specific inhibitor of mitogen activated protein kinase kinase (MEK or MAPKK), on migration and invasion in SACC-LM cells, showing U0126 not only inactivated ERK1/2, but also inhibited migration and invasion of SACC-LM. The present findings suggested that the elevated expression of activated ERK1/2 may play a role in lung metastasis of salivary adenoid cystic carcinoma.
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PMID:Relationship of activated extracellular signal-regulated kinase 1/2 with lung metastasis in salivary adenoid cystic carcinoma. 1908 54

The role of erythropoietin receptor (EpoR) expression in tumor cells and the potential of EpoR-mediated signaling to contribute to cellular proliferation and invasiveness require further characterization. To determine whether EpoR expression and activation in tumor cells modulates intracellular signal transduction to promote cellular proliferation and migration, we employed a novel experimental model using human breast cancer cells engineered to stably express a constitutively active EpoR-R129C variant. EpoR-R129C expression resulted in increased cellular proliferation and migration of breast cancer cells and these effects were associated with significantly increased Epo-induced phosphorylation of ERK1/2, AKT and c-Jun-NH2-kinase (SAPK/JNK) proteins. Expression of the constitutively active EpoR-R129C receptor promoted the proliferation and migration of breast cancer cells via activation of ERK- and SAPK/JNK-dependent signaling pathways, respectively. These findings suggest that EpoR over-expression and activation in breast cancer cells has the potential to contribute to tumor progression by promoting the proliferation and invasiveness of the neoplastic cells.
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PMID:Constitutively active erythropoietin receptor expression in breast cancer cells promotes cellular proliferation and migration through a MAP-kinase dependent pathway. 1913 31

Gliomas are the most common and lethal tumor type in the brain. The present study investigated the effect of oligomer procyanidins (F2) (F2, degree of polymerization 2-15), a natural fraction isolated from grape seeds on the biological behavior of glioblastoma cells. We found that F2 significantly inhibited the glioblastoma growth, with little cytotoxicity on normal cells, induced G2/M arrest and decreased mitochondrial membrane potential in U-87 cells. It also induced a non-apoptotic cell death phenotype resembling paraptosis in U-87 cells. In addition, it was found for the first time that F2 in non-cytotoxic concentrations selectively inhibited U-87 cell chemotaxis mediated by a G-protein coupled receptor formyl peptide receptor FPR, which is implicated in tumor cell invasion and metastasis. Further experiments indicated that F2 inhibited fMLF-induced U-87 cell calcium mobilization and MAP kinases ERK1/2 phosphorylation. Moreover, F2 attenuated the glioblastoma FPR expression, a new molecular target for glioma therapeutics, which has been shown to play important roles in glioma cells chemotaxis, proliferation and angiogenesis in addition to its promotion to tumor progression, but did not affect FPR mRNA expression in U-87 cells. Taken together, our results suggest that F2 may be a promising candidate for the development of novel anti-tumor therapeutics.
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PMID:Inhibition of U-87 human glioblastoma cell proliferation and formyl peptide receptor function by oligomer procyanidins (F2) isolated from grape seeds. 1916 69

Most types of prostate cancer (PCa) are usually initially responsive to androgenic regulation and, therefore, to androgen ablation therapy. However, in several patients tumors may progress to androgen resistance and be poorly responsive to any therapy. Many factors may account for this progression to androgen independence, including increased responsiveness to estrogens and peptide growth factors. The role of estrogens in androgen independence has been suggested by the observation that both primary and metastatic PCa express the estrogen receptor (ER-beta), a recently discovered ER subtype. On the other hand, peptide growth factors, like IGF-1, IGF-2, and the insulin-like growth factor receptor (IGF-1R), may play a role in regulating growth, survival, and invasion of PCa cells. Here, we show that both androgens and estrogens markedly upregulate the IGF-1R expression in PCa cells by activating a nongenotropic pathway and sensitizing cells to the biological effects of IGF-1. This effect is specific for IGF-1R because it does not involve the highly homologous insulin receptor. IGF-1R upregulation is caused by increased mRNA transcription. However, it does not require steroid receptor binding to DNA, but involves AR and ER binding to c-Src and subsequent activation of ERK1/2 and other cytoplasmatic kinases, which eventually stimulate IGF-1R promoter activity. In conclusion, our data indicate that both androgens and estrogens contribute to IGF system deregulation in PCa and may play a role in tumor progression to androgen independence. Inhibition of the IGF-1R or the Src-ERK pathway should be considered, therefore, as an adjuvant therapy in PCa.
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PMID:Sex steroids upregulate the IGF-1R in prostate cancer cells through a nongenotropic pathway. 1925 Feb 14

Proliferation and apoptosis of endothelial cells are crucial angiogenic processes that contribute to carcinogenesis and tumor progression. Emerging evidence implicates the regulation of proliferation and apoptosis by reactive oxygen species (ROS) such as superoxide and hydrogen peroxide (H(2)O(2)). In the present study, we investigated the roles of the ROS-generating Nox4- and Nox2-containing reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases in proliferation of human endothelial cells by examining the impact of these enzyme systems on (1) specific proliferative and tumorigenic kinases, extracellular regulated kinase1/2 (ERK1/2) and Akt, (2) cytoskeletal organization, and (3) the mechanisms that influence cellular apoptosis. ROS production and the expression of NADPH oxidase subunit Nox4, but not Nox2, were markedly higher in proliferating than in quiescent endothelial cells. Addition of the H(2)O(2) scavenger catalase or downregulation of Nox4 protein with specific siRNA reduced ROS levels, cell proliferation, and ERK1/2 phosphorylation but had no effect on either cell morphology or caspase 3/7 activity. Although downregulation of Nox2 protein with siRNA also reduced ROS production and cell proliferation, it caused an increase in caspase 3/7 activity, reduced Akt phosphorylation, and caused cytoskeletal disorganization. Therefore, in endothelial cells, Nox4-derived H(2)O(2) activates ERK1/2 to promote proliferation, whereas Nox2-containing NADPH oxidase maintains the cytoskeleton and prevents apoptosis to support cell survival. Our study provides a new understanding of the molecular mechanisms that underpin endothelial cell survival and a rationale for the combined suppression of Nox4- and Nox2-containing NADPH oxidases for unwanted angiogenesis in cancer.
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PMID:NADPH oxidase isoform selective regulation of endothelial cell proliferation and survival. 1933 23

Hypoxia-inducible factor-1 (HIF-1) plays a central role in tumor progression by regulating genes involved in proliferation, glycolysis, angiogenesis, and metastasis. To improve our understanding of HIF-1 regulation by kinome, we screened a kinase-specific small interference RNA library using a hypoxia-response element (HRE) luciferase reporter assay under hypoxic conditions. This screen determined that depletion of cellular SMG-1 kinase most significantly modified cellular HIF-1 activity in hypoxia. SMG-1 is the newest and least studied member of the phosphoinositide 3-kinase-related kinase family, which consists of ATM, ATR, DNA-PKcs, mTOR, and SMG-1. We individually depleted members of the phosphoinositide 3-kinase-related kinase family, and only SMG-1 deficiency significantly augmented HIF-1 activity in hypoxia. We subsequently discovered that SMG-1 kinase activity was activated by hypoxia, and depletion of SMG-1 up-regulated MAPK activity under low oxygen. Suppressing cellular MAPK by silencing ERK1/2 or by treatment with U0126, a MAPK inhibitor, partially blocked the escalation of HIF-1 activity resulting from SMG-1 deficiency in hypoxic cells. Increased expression of SMG-1 but not kinase-dead SMG-1 effectively inhibited the activity of HIF-1alpha. In addition, cellular SMG-1 deficiency increased secretion of the HIF-1alpha-regulated angiogenic factor, vascular epidermal growth factor, and survival factor, carbonic anhydrase IX (CA9), as well as promoted the hypoxic cell motility. Taken together, we discovered that SMG-1 negatively regulated HIF-1alpha activity in hypoxia, in part through blocking MAPK activation.
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PMID:Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia. 1940 46

Transitional cell carcinoma (TCC) is the most common form of bladder cancer. In bladder cancer, which in terms of its origins and genetics, is a representative of invasive tumors, the differing clinical course and the limited value of established prognostic markers compelled many researchers to look for new molecular parameters in predicting the prognosis and treatment of patients with bladder cancer. Activation of mitogen activated protein kinase (MAPK) is a frequent event in tumor progression and metastasis. In the current study, we investigated the role of two different MAPKs (ERK1/2 and p38) by using their specific inhibitors PD98059 and SB203580 respectively, on bladder cancer growth in two cell lines derived from different tumor stages. Our preliminary work showed that ERK1/2 and p38 MAP kinase are active during the log phase growth of bladder cancer, and inhibition of these pathways could reduce proliferation and growth. Moreover, treatment with these inhibitors hinders DNA synthesis, and has differential effects on the progression of cell cycle. ERK1/2 inhibitor caused cyclin B1-dependent G2/M arrest in both HTB5 and HTB9 bladder cancer cell lines, where as p38 MAPK inhibitor showed G2/M arrest in HTB9 and G1 arrest in HTB5 cell line. Furthermore, decreased proliferation and growth arrest caused by MAPK inhibitors was found to be a reflection of apoptotic induction by these inhibitors in bladder cancer cells. Thus, these studies establish MAPKs as a molecular target in bladder cancer growth which could provide new molecular modalities in clinical application.
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PMID:Differential effects of MAPKs signaling on the growth of invasive bladder cancer cells. 1942 73

PED/PEA-15 is a 15-kDa ubiquitously expressed protein implicated in a number of fundamental cellular functions, including apoptosis, proliferation, and glucose metabolism. PED/PEA-15 lacks enzymatic function and serves mainly as a molecular adaptor. PED/PEA-15 is an endogenous substrate for protein kinase C (PKC), calcium/calmodulin-dependent protein kinase II (CAM kinase II), and Akt. In particular, PKC phosphorylates PED/PEA-15 at Ser(104) and CAM kinase II or Akt at Ser(116), modifying its stability. Evidence obtained over the past 10 years has indicated that PED/PEA-15 regulates cell survival by interfering with both intrinsic and extrinsic apoptotic pathways. In addition, it may also control cell proliferation by interfering with ERK1/2-mediated pathways. Indeed, PED/PEA-15 has been identified as an ERK1/2 interactor, which modifies its subcellular localization and targeting to a specific subset of substrates. Increased PED/PEA-15 levels may affect tumorigenesis and cancer progression as well as sensitivity to anticancer agents. Moreover, PED/PEA-15 affects astrocyte motility and increases susceptibility to skin carcinogenesis in vivo. PED/PEA-15 expression is regulated at the transcriptional and the posttranslational levels. Increased PED/PEA-15 expression has been identified in individuals with type 2 diabetes early during the natural history of the disease. Evidence generated over the past 10 years indicated that this defect contributes to altering glucose tolerance by impairing insulin action and insulin secretion and might play a role in the development of diabetes-associated neurological disorders. Strategies are being devised to target key signaling events in PED/PEA-15 action aimed at improving glucose tolerance and at facilitating cancer cell death.
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PMID:Frontiers: PED/PEA-15, a multifunctional protein controlling cell survival and glucose metabolism. 1953 39


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