Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tiam1 activates the Rho-like GTPase Rac1, and studies indicate that Tiam1-Rac1 signaling affects invasion in different ways depending on the cell type studied. However, no investigations on Tiam1 in human tumors have been reported. Here, we show that for 4 of 5 human renal-cell carcinoma (RCC) cell lines the expression levels of Tiam1 tended to be inversely correlated with in vitro invasiveness, whereas no obvious correlation could be found between the expression levels of Rac1 and invasion. Subsequent mutation analysis of these cell lines revealed no mutations in Rac1 but up to 5 different point mutations in the Tiam1 gene. Of these, 1 mutation (A441G) was located in the NH2-terminal pleckstrin homology domain, which is essential for membrane localization and functional activity of Tiam1. By analysis of an additional 30 primary human RCCs, mutation A441G was found in 4 of 35 tumors and tumor cell lines (11.5%) but not in the respective normal kidney tissues. By enzymatic digestion, mutation A441G proved to be heterozygous, suggesting a dominant active function. This was supported by showing that stable over-expression of mutated A441G-Tiam1 induced transformation of NIH3T3 cells, as determined in a colony formation assay, whereas empty vector and wild-type Tiam1 failed to do so. In conclusion, a distinct Tiam1 mutation (A441G) was identified in several human RCCs. This mutation induced transformation of NIH3T3 cells and, hence, might play a major role in the progression of human RCCs. Further analyses on Tiam1 mutations in human tumors might give new clues to their role in tumor progression.
Int J Cancer 2000 Nov 01
PMID:Tiam1 mutations in human renal-cell carcinomas. 1105 65

Sphingosine 1-phosphate (S1P) is stored in and released from platelets in response to cell activation. However, recent studies show that it is also released from a number of cell types, where it can function as a paracrine/autocrine signal to regulate cell proliferation, differentiation, survival, and motility. This review discusses the role of S1P in cellular regulation, both at the molecular level and in terms of health and disease. The main biochemical routes for S1P synthesis (sphingosine kinase) and degradation (S1P lyase and S1P phosphatase) are described. The major focus is on the ability of S1P to bind to a novel family of G-protein-coupled receptors (endothelial differentiation gene [EDG]-1, -3, -5, -6, and -8) to elicit signal transduction (via G(q)-, G(i)-, G(12)-, G(13)-, and Rho-dependent routes). Effector pathways regulated by S1P are divergent, such as extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, phospholipases C and D, adenylyl cyclase, and focal adhesion kinase, and occur in multiple cell types, such as immune cells, neurones, smooth muscle, etc. This provides a molecular basis for the ability of S1P to act as a pleiotropic bioactive lipid with an important role in cellular regulation. We also give an account of the expanding role for S1P in health and disease; in particular, with regard to its role in atherosclerosis, angiogenesis, cancer, and inflammation. Finally, we describe future directions for S1P research and novel approaches whereby S1P signalling can be manipulated for therapeutic intervention in disease.
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PMID:Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors. 1115 May 92

Members of the integrin family of cell adhesion receptors influence several important aspects of cancer cell behavior, including motility and invasiveness, cell growth, and cell survival. Engagement of integrins with extracellular matrix (ECM) proteins can activate members of the Rho-family of small GTPases; conversely, Rho- and Ras-family proteins can influence the ability of integrins to bind their ligands. These events impinge on the control of cell motility, and ultimately on invasive and metastatic behavior. Integrin engagement with ECM also has important effects on cell survival, particularly for cells of epithelial origin. In some cases, specific integrins have selective effects on the efficiency of signal transduction in cell survival pathways.
Semin Cancer Biol 2000 Dec
PMID:New aspects of integrin signaling in cancer. 1117 Aug 63

Farnesyltransferase (FTase) inhibitors are among the current wave of molecularly targeted anti-cancer agents being used to attack malignancy in a rational manner. A large body of preclinical data indicates that FTase inhibitors block cancer cell proliferation through both cytostatic and cytotoxic effects. Interestingly, FTase inhibitors have rather limited effects on normal cell function, suggesting that they may target unique aspects of cancer cell pathophysiology. The development of FTase inhibitors was predicated on the discovery that the Ras oncoproteins must be post-translationally modified to transform cells. However, recent work indicates that the anti-neoplastic effects of FTase inhibitors depend on altering the post-translational modifications of non-Ras proteins as well. In particular, a critical target protein that responds to FTase inhibition by blocking tumor cell growth is RhoB, an endosomal Rho protein that functions in receptor trafficking. In this review, we survey the biological foundations for the clinical development of FTase inhibitors, and consider some of the latest mechanistic studies that reveal how these agents affect cellular physiology.
Semin Cancer Biol 2000 Dec
PMID:Farnesyltransferase inhibitors: antineoplastic properties, mechanisms of action, and clinical prospects. 1117 Aug 66

Gastrin, produced by G cells in the gastric antrum, has been identified as the circulating hormone responsible for stimulation of acid secretion from the parietal cell. Gastrin also acts as a potent cell-growth factor that has been implicated in a variety of normal and abnormal biological processes including maintenance of the gastric mucosa, proliferation of enterochromaffin-like cells, and neoplastic transformation. Here, we review the models used to study the effects of gastrin on cell proliferation in vivo and in vitro with respect to mechanisms by which this hormone might influence normal and cancerous cell growth. Specifically, human and animal models of hypergastrinemia and hypogastrinemia have been described in vivo, and several cells that express cholecystokinin (CCK)B/gastrin receptors have been used for analysis of intracellular signaling pathways initiated by biologically active amidated gastrins. The binding of gastrin or CCK to their common cognate receptor triggers the activation of multiple signal transduction pathways that relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades, including mitogen-activated protein kinase, is an important early response to these signaling peptides. Gastrin and CCK also induce rapid Rho-dependent actin remodeling and coordinate tyrosine phosphorylation of cellular proteins including the non-receptor tyrosine kinases p125fak and Src and the adaptor proteins p130cas and paxillin. This article reviews recent advances in defining the role of gastrin and CCK in the control of cell proliferation in normal and cancer cells and in dissecting the signal transduction pathways that mediate the proliferative responses induced by these hormonal GI peptides in a variety of normal and cancer cell model systems.
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PMID:Gastrin, CCK, signaling, and cancer. 1118 48

A long-standing goal in cancer research is to identify cellular functions that have selective roles in regulating neoplastic pathophysiology. Farnesyl-transferase inhibitors (FTIs) are a novel class of cancer chemotherapeutics which have little effect on normal cell physiology but which inhibit or reverse malignant cell phenotypes. FTIs were originally developed as a strategy to inhibit oncogenic Ras, the activity of which depends upon posttranslational farnesylation. However, recent work indicates the antineoplastic effects of FTIs are not linked to Ras inhibition but instead to alteration of RhoB, a small GTPase of the Rho family of cytoskeletal regulators that controls trafficking of cell surface receptors. Rho proteins integrate signals from integrins and cytokine receptors with cell shape via the actin cytoskeleton. A connection between FTIs and Rho alteration is interesting given that histological differences have long been used to define clinical cancer. RhoB is dispensable for normal cell growth and differentiation in mice. Thus, research into the antineoplastic effects of FTIs has led to the identification of a function(s) that is unnecessary for normal cell physiology but crucial for controlling malignant phenotypes.
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PMID:Farnesyltransferase inhibitors define a role for RhoB in controlling neoplastic pathophysiology. 1119 2

Ras and Rho GTPases are among the best studied signaling molecules in molecular biology. Essential cellular processes, such as cell growth, lipid metabolism, cytoarchitecture, membrane trafficking, transcriptional regulation, apoptosis, and response to genotoxic agents, are directly modulated by different members of this superfamily of proteins. Not until recently have we begun to understand the physiological implications of Ras and Rho GTPases, linking them to processes such as embryonic development, tissue remodeling, tumorigenesis and metastasis. In this sense, uncontrolled activation, due to overexpression of different members of the Rho family in a variety of tissues, leads to uncontrolled proliferation and invasiveness of human tumors. In this review, an attempt to briefly integrate recent findings in transcriptional regulation by Rho GTPases in the context of carcinogenesis and metastasis as well as apoptosis is made.
Cancer Lett 2001 Apr 10
PMID:Rho signals to cell growth and apoptosis. 1124 12

Signal transduction pathways controlling spontaneous locomotion of Walker carcinosarcoma cells are not well understood. We have therefore investigated the role of signalling proteins in development of polarity and locomotion of these cells. Treatment of the cells with 100 ng/ml pertussis toxin had no significant effect on the percentage of polarized cells. In contrast, 2 different phosphatidylinositol 3-kinase inhibitors (wortmannin and LY-294002) markedly reduced the proportion of polarized cells. Spontaneous locomotion of the cells was also significantly inhibited by these two inhibitors. In agreement with these data, we observed localization of the p85alpha subunit of phosphatidylinositol 3-kinase predominantly in the membrane fraction of Walker carcinosarcoma cells, indicating constitutive activation of this enzyme. We also investigated a role of Rho family proteins. Spontaneous development of polarity was almost completely suppressed by electroporation of the cells in the presence of 4 microg/ml C(3) exoenzyme, which specifically ADP-ribosylates and inactivates Rho. Two downstream targets of Rho, the Rho-activated kinases I and II, were also detected predominantly in the particulate membrane fraction, suggesting constitutive activation. A specific Rho-kinase inhibitor (Y-27632) blocked spontaneous polarization and migration in a concentration-dependent manner. Our results indicate that constitutive activation of the Rho/Rho-kinase pathway and of phosphatidylinositol 3-kinase plays an essential part in spontaneous development of polarity and cell locomotion of these cells.
Int J Cancer 2001 Mar 15
PMID:The Rho/Rho-kinase and the phosphatidylinositol 3-kinase pathways are essential for spontaneous locomotion of Walker 256 carcinosarcoma cells. 1127 77

Down-regulation of E-cadherin function is characteristic of cancer cells and might involve the small G-protein Rho family, including Rac1 and Cdc42. IQGAP1 has been reported to be one of the target proteins of Rac1 and Cdc42. To elucidate the role of IQGAP1 in cancer-cell adhesion, its expression was investigated in 47 cases of human gastric cancer by immunohistochemistry and Western blot upon protein fractionation, especially in comparison with E-cadherin and catenin expression. In the non-cancerous columnar epithelium of the stomach, IQGAP1, as well as E-cadherin/catenin, was expressed at the cell-cell boundary. IQGAP1 was frequently observed diffusely in the cytoplasm in intestinal-type tumors (20/22 cases) but was expressed at the cell membrane in diffuse-type tumors (19/25 cases), thus showing significant association with tumor differentiation (p < 0.01). Interestingly, membranous expression of IQGAP1 was inversely correlated with that of E-cadherin (p < 0.05) or alpha-catenin (p < 0.001). These observations were consistent with the Western blot results following protein fractionation. IQGAP1 was dominantly expressed in the soluble fraction in differentiated tumors; however, in undifferentiated tumors, it was mostly in the insoluble fraction. In contrast, both E-cadherin and alpha-catenin were detected only in the insoluble fraction. Thus, subcellular localization of IQGAP1 from the cytoplasm to the cell membrane was correlated with E-cadherin dysfunction and tumor dedifferentiation in gastric carcinogenesis.
Int J Cancer 2001 Mar 15
PMID:Localization of IQGAP1 is inversely correlated with intercellular adhesion mediated by e-cadherin in gastric cancers. 1127 80

Garcinol, a polyisoprenylated benzophenone, was purified from Garcinia indica fruit rind. The effects of garcinol and curcumin on cell viability in human leukemia HL-60 cells were investigated. Garcinol and curcumin displayed strong growth inhibitory effects against human leukemia HL-60 cells, with estimated IC(50) values of 9.42 and 19.5 microM, respectively. Garcinol was able to induce apoptosis in a concentration- and time-dependent manner; however, curcumin was less effective. Treatment with garcinol caused induction of caspase-3/CPP32 activity in a dose- and time-dependent manner, but not caspase-1 activity, and induced the degradation of poly(ADP-ribose) polymerase (PARP). Pretreatment with caspase-3 inhibitor inhibited garcinol-induced DNA fragmentation. Treatment with garcinol (20 microM) caused a rapid loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. The cleavage of D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, occurred simultaneously with the activation of caspase-3 but preceded DNA fragmentation and the morphological changes associated with apoptotic cell death. Of these, Bcl-2, Bad, and Bax were studied. The level of expression of Bcl-2 slightly decreased, while the levels of Bad and Bax were dramatically increased in cells treated with garcinol. These results indicate that garcinol allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. It is suggested that garcinol-induced apoptosis is triggered by the release of cytochrome c into the cytosol, procaspase-9 processing, activation of caspase-3 and caspase-2, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by garcinol may provide a pivotal mechanism for its cancer chemopreventive action.
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PMID:Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells. 1131 81


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