Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analysis of metastatic prostate cancers has identified the Raf kinase inhibitory protein (RKIP) as a suppressor of metastases. Previous studies demonstrated that RKIP binds to Raf-1 and prevents the activation of the extracellular regulated kinase (ERK) cascade. New work shows that phosphorylation of RKIP by protein kinase C disassociates RKIP from Raf-1 and stimulates its binding to, and inhibition of G-protein-coupled receptor kinase 2 (GRK2). This switching enhances signaling by activation of the ERK pathway and by decreased receptor desensitization.
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PMID:Killing two birds with one RKIP. 1514 72

The alpha6beta1 integrin has been implicated in breast carcinoma progression, but the mechanisms involved remain elusive. MDA-MB-435 cells engineered to be deficient in alpha6beta1 expression form primary tumors that are highly apoptotic and unable to metastasize, although they exhibit no increased apoptosis in vitro under standard culture conditions. Based on the hypothesis that alpha6beta1 is necessary for the survival of these cells in the tumor microenvironment, we report here that hypoxia protects these cells from apoptosis induced by serum deprivation and that hypoxia-mediated protection requires alpha6beta1 expression. We investigated the influence of alpha6beta1 on vascular endothelial growth factor (VEGF) expression because autocrine VEGF is necessary for the survival of serum-deprived cells in hypoxia. The results obtained indicate that alpha6beta1 is necessary for VEGF expression because the ability of hypoxia to activate HIF-1 and to stimulate VEGF transcription in MDA-MB-435 cells is dependent on alpha6beta1 expression by a mechanism that involves protein kinase C-alpha.
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PMID:Hypoxia-induced vascular endothelial growth factor transcription and protection from apoptosis are dependent on alpha6beta1 integrin in breast carcinoma cells. 1525 36

Tumor metastasis is the major cause of morbidity and mortality in patients with breast cancer. It is critical to identify metastasis enabling genes and understand how they are responsible for inducing specific aspects of the metastatic phenotype to allow for improved clinical detection and management. Protein kinase C epsilon (PKC epsilon), a member of a family of serine/threonine protein kinases, is a transforming oncogene that has been reported to be involved in cell invasion and motility. In this study, we investigated the role of PKC epsilon in breast cancer development and progression. High-density tissue microarray analysis showed that PKC epsilon protein was detected in 73.6% (106 of 144) of primary tumors from invasive ductal breast cancer patients. Increasing PKC epsilon staining intensity was associated with high histologic grade (P = 0.0206), positive Her2/neu receptor status (P = 0.0419), and negative estrogen (P = 0.0026) and progesterone receptor status (P = 0.0008). Kaplan-Meier analyses showed that PKC epsilon was significantly associated with poorer disease-free and overall survival (log-rank, P = 0.0478 and P = 0.0414, respectively). RNA interference of PKC epsilon in MDA-MB231 cells, an aggressive breast cancer cell line with elevated PKC epsilon levels, resulted in a cell phenotype that was significantly less proliferative, invasive, and motile than the parental or the control RNA interference transfectants. Moreover, in vivo tumor growth of small interfering RNA-PKC epsilon MDA-MB231 clones was retarded by a striking 87% (P < 0.05) and incidence of lung metastases was inhibited by 83% (P < 0.02). PKC epsilon-deficient clones were found to have lower RhoC GTPase protein levels and activation. Taken together, these results revealed that PKC epsilon plays a critical and causative role in promoting an aggressive metastatic breast cancer phenotype and as a target for anticancer therapy.
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PMID:Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. 1616 14

This review examines the hypothesis that the function of the alpha 6beta 4 integrin is altered substantially as normal epithelia undergo malignant transformation and progress to invasive carcinoma and that the functions of this integrin contribute to the behavior of aggressive carcinoma cells. Specifically, alpha 6beta 4 functions primarily as an adhesion receptor in normal epithelia, often as a component of hemidesmosomes and associated with intermediate filaments. Factors in the host-tumor microenvironment have the potential to mobilize alpha 6beta 4 from hemidesmosomes and promote its association with F-actin in lamellae and filopodia, a process that is mediated by PKC-dependent phosphorylation of the beta 4 cytoplasmic domain. Importantly, this altered localization of alpha 6beta 4 appears to be coupled to an activation of its signaling potential, which may occur through its association with growth factor receptors or lipid rafts, possibilities that are not mutually exclusive. The primal signaling event triggered by alpha 6beta 4 appears to be activation of PI3-K and this activation has profound consequences on the migration, invasion and survival of carcinoma cells. Arguably, the ability of alpha 6beta 4 to stimulate the PI3-K-dependent translation of VEGF and possibly other growth factors may be the most significant contribution of this integrin to carcinoma because of the potential autocrine and paracrine effects of these factors.
Cancer Metastasis Rev 2005 Sep
PMID:Mobilization and activation of a signaling competent alpha6beta4integrin underlies its contribution to carcinoma progression. 1625 29

Metastasis is a vital target for cancer treatment, since the majority of cancer patients die from metastatic, rather than the primary disease. KiSS1 has been identified as a metastasis suppressor gene in melanoma and breast carcinomas. We show here that KiSS1 is also a metastasis suppressor in human ovarian cancer. Overexpression of KiSS1 in ovarian cancer cells inhibits cell migration induced by serum or lysophosphatidic acid (LPA), and colonization in soft agar, but not cell proliferation, representing the characteristics of a metastasis suppressor gene. Furthermore, using an experimental metastatic mouse model, we show that expression of KiSS1 in SKOV3 ovarian cancer cells suppresses >50% metastatic colonization in mice (P < 0.0001). We find that activating protein kinase C (PKC) reverses about 80% of the inhibited cell migration induced by KiSS1, while down-regulation of PKCalpha with shRNA restores KiSS1 effect, providing evidence that inhibiting PKCalpha may be an important mechanism of the effect of KiSS1. These results suggest that KiSS1 is a metastasis suppressor of ovarian cancer and may be a potential molecular target for the treatment.
Clin Exp Metastasis 2005
PMID:KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha. 1628 80

Drinking green tea is associated with decreased frequency of cancer development. This review outlines the wide range of mechanisms by which epigallocatechin gallate (ECGC) and other green and black tea polyphenols inhibit cancer cell survival. EGCG suppressed androgen receptor expression and signalling via several growth factor receptors. Cell cycle arrest or apoptosis involved caspase activation and altered Bcl-2 family member expression. EGCG inhibited telomerase activity and led to telomere fragmentation. While at high concentrations polyphenols had pro-oxidative activities, at much lower levels, anti-oxidative effects occurred. Nitric oxide production was reduced by EGCG and black tea theaflavins by suppressing inducible nitric oxide synthase via blocking nuclear translocation of the transcription factor nuclear factor-kappaB as a result of decreased IkappaB kinase activity. Polyphenols up- or down-regulated activity of a number of key enzymes, including mitogen-activated protein kinases and protein kinase C, and increased or decreased protein/mRNA levels, including that of cyclins, oncogenes, and tumor suppressor genes. Metastasis was inhibited via effects on urokinase and matrix metalloproteinases. Polyphenols reduced angiogenesis, in part by decreasing vascular endothelial growth factor production and receptor phosphorylation. Recent work demonstrated that EGCG reduced dihydrofolate reductase activity, which would affect nucleic acid and protein synthesis. It also acted as an aryl hydrocarbon receptor an-tagonist by directly binding the receptor's molecular chaperone, heat shock protein 90. In conclusion, green and black tea polyphenols act at numerous points regulating cancer cell growth, survival, and metastasis, including effects at the DNA, RNA, and protein levels.
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PMID:Mechanisms of cancer prevention by green and black tea polyphenols. 1701 50

Over 70% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced stage III and IV disease. In spite of aggressive therapy, locoregional disease recurs in 60% and metastatic disease develops in 15% to 25% of patients causing a major decline in quality and length of life. Therefore, there is a need to identify and understand genes that are responsible for inducing an aggressive HNSCC phenotype. Evidence has shown that protein kinase C (PKC) epsilon is a transforming oncogene and may play a role in HNSCC progression. In this study, we determine the downstream signaling pathway mediated by PKC epsilon to promote an aggressive HNSCC phenotype. RNA interference knockdown of PKC epsilon in UMSCC11A and UMSCC36, two highly invasive and motile HNSCC cell lines with elevated endogenous PKC epsilon levels, resulted in cells that were significantly less invasive and motile than the small interfering RNA-scrambled control transfectants; 51 +/- 5% (P < 0.006) and 49 +/- 3% (P < 0.010) inhibition in invasion and 69 +/- 1% (P < 0.0005) and 66 +/- 3% (P < 0.0001) inhibition in motility, respectively. PKC epsilon-deficient UMSCC11A clones had reduced levels of active and serine-phosphorylated RhoA and RhoC. Moreover, constitutive active RhoA completely rescued the invasion and motility defect, whereas constitutive active RhoC completely rescued the invasion and partially rescued the motility defect of PKC epsilon-deficient UMSCC11A clones. These results indicate that RhoA and RhoC are downstream of PKC epsilon and critical for PKC epsilon-mediated cell invasion and motility. Our study shows, for the first time, that PKC epsilon is involved in a coordinated regulation of RhoA and RhoC activation, possibly through direct post-translational phosphorylation.
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PMID:Targeted disruption of protein kinase C epsilon reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinoma. 1701 91

In previous studies, we found that IFNgamma and TNFalpha generated by activated macrophages stimulate the metastatic potential in F10-M3 cells, a clone isolated from B16-F10 murine melanoma line. In this phenomenon, TNFalpha promoted the expression of a metastatic phenotype in tumor cells previously primed with IFNgamma. Here, we demonstrate that IFNalpha or IFNbeta may replace IFNgamma in priming tumor cells. We also noticed that an enhancement of the expression of p55TNFalpha receptor was associated with the preconditioning of tumor cells with IFNgamma and IFNbeta. By the use of an appropriate inhibitor, we observed that JAK1 signal transduction pathway was involved in the expression of a metastatic phenotype and of p55TNFalpha receptor shown in IFNgamma- and IFNbeta-primed melanoma cells stimulated with TNFalpha. Furthermore, the activity of the protein kinase C (PKC) was required for IFNgamma-primed melanoma cells to express a metastatic phenotype after stimulation with TNFalpha. In conclusion, our study shows that a metastatic phenotype was expressed in B16 murine melanoma cells stimulated with TNFalpha regardless of whether the cells were primed with IFNgamma IFNalpha or IFNbeta. The molecular events leading to the expression of a metastatic phenotype in F10-M3 melanoma cells are represented by: (a) an enhanced expression of p55TNFalpha receptor in IFNs-primed tumor cells dependent on JAK1 signal transduction pathway; and (b) an intact PKC activity during TNFalpha stimulation.
Clin Exp Metastasis 2006
PMID:Expression of a metastatic phenotype in IFNs-primed/TNFalpha-activated B16 murine melanoma cells: role of JAK1/PKCdelta signal transduction factors. 1702 22

Reactive oxygen species (ROS) are recently proposed to be involved in tumor metastasis which is a complicated processes including epithelial-mesenchymal transition (EMT), migration, invasion of the tumor cells and angiogenesis around the tumor lesion. ROS generation may be induced intracellularly, in either NADPH oxidase- or mitochondria-dependent manner, by growth factors and cytokines (such as TGFbeta and HGF) and tumor promoters (such as TPA) capable of triggering cell adhesion, EMT and migration. As a signaling messenger, ROS are able to oxidize the critical target molecules such as PKC and protein tyrosine phosphates (PTPs), which are relevant to tumor cell invasion. PKC contain multiple cysteine residues that can be oxidized and activated by ROS. Inactivation of multiple PTPs by ROS may relieve the tyrosine phosphorylation-dependent signaling. Two of the down-stream molecules regulated by ROS are MAPK and PAK. MAPKs cascades were established to be a major signal pathway for driving tumor cell metastasis, which are mediated by PKC, TGF-beta/Smad and integrin-mediated signaling. PAK is an effector of Rac-mediated cytoskeletal remodeling that is responsible for cell migration and angiogenesis. There are several transcriptional factors such as AP1, Ets, Smad and Snail regulating a lot of genes relevant to metastasis. AP-1 and Smad can be activated by PKC activator and TGF-beta1, respectively, in a ROS dependent manner. On the other hand, Est-1 can be upregulated by H2O2 via an antioxidant response element in the promoter. The ROS-regulated genes relevant to EMT and metastasis include E-cahedrin, integrin and MMP. Comprehensive understanding of the ROS-triggered signaling transduction, transcriptional activation and regulation of gene expressions will help strengthen the critical role of ROS in tumor progression and devising strategy for chemo-therapeutic interventions.
Cancer Metastasis Rev 2006 Dec
PMID:The signaling mechanism of ROS in tumor progression. 1716 Jul 8

The development of a primary tumor as such is not the main cause of death, but is rather the spreading of metastases, which causes over 90% of deaths in cancer patients. This largely depends on the ability of tumor cells to migrate away from the tumor and relocate at other areas of the body. Cell migration is known to be regulated by various extracellular signal substances such as neurotransmitters. However, before single tumor cells can start to invade into distant tissue, they have to dissociate from the primary tumor. This requires the disruption of cell-cell contacts, which are provided by a plethora of adhesion molecules like the family of cadherins. Using our well, established three-dimensional collagen-based cell migration assay, we show that engagement of N-cadherin results in a significant decrease of the spontaneous and the norepinephrine-induced migration of MDA-MB-468 breast carcinoma cells, which was due to an increase in the average break length. Moreover, this N-cadherin driven influence on the migratory activity is intracellularly integrated via multiple signaling pathways. Our results show that the impact of N-cadherin on the locomotion of MDA cells involves the activation of the adenylyl cyclase and the phosphatidylinositol-3-kinase (PI3K), but is independent of the protein kinase C (PKC) alpha. In summary, we provide evidence that the engagement of N-cadherin provides a stop signal for breast carcinoma cell migration, and accordingly the use of anti-N-cadherin antibodies or soluble ligands might be a tool to inhibit metastasis formation in E-cadherin negative but N-cadherin positive tumors.
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PMID:N-cadherin engagement provides a dominant stop signal for the migration of MDA-MB-468 breast carcinoma cells. 1717 Dec 99


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