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)

ARHI (Ras homologue member I) encodes a 26-kDa GTPase with 50-60% amino acid homology to Ras and Rap. ARHI and Ras share similar GTP/GDP binding domains, but exert opposite functions. ARHI is one of the first reported tumor suppressors in the ras superfamily. ARHI is expressed consistently in normal breast and ovarian epithelial cells, but not in breast or ovarian cancers. The loss of ARHI can be related to tumor progression. Reexpression of ARHI induces apoptosis of breast and ovarian cancer cells by a caspase-independent, calpain-dependent pathway. ARHI is consistently expressed in normal breast and ovarian epithelial cells but is dramatically downregulated in more then 70% of breast and ovarian cancers. ARHI is maternally imprinted with methylation of the three CpG islands in the maternal allele of normal cells. ARHI is expressed only from the paternal allele whose three CpG islands are not methylated. Loss of ARHI expression can occur through a genetic event, with loss of heterozygosity observed in 40% of breast, ovarian, and pancreatic cancers; but it can also occur through epigenetic mechanisms, including DNA methylation, histone deacetylation, histone methylation, and transcriptional regulation. Our data suggest that acetylation and methylation of chromatin associated with the ARHI promoter leads to loss of both ARHI expression and the ability to suppress tumor growth. Changes in chromatin that silence ARHI may be driven by methylation-dependent and -independent pathways. Reactivation of both the silenced paternal and imprinted maternal alleles can be achieved by demethylation and inhibition of histone deacetylation.
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PMID:Epigenetic regulation of ARHI in breast and ovarian cancer cells. 1272 31

Activating mutations of Ras have been implicated in approximately 30% of human cancers. In every case, the biochemical consequence of such mutations is to disrupt the GTPase activity of Ras and to render Ras resistant to the actions of GTPase activating proteins. Consequently, oncogenic Ras mutants are "locked" in a GTP-bound active state. We detected a potent activity in Escherichia coli extract that can efficiently convert mutationally activated GTP-bound Ras to the inactive GDP-bound form. Purification of the protein responsible for this activity led to the identification of the enzyme nucleoside diphosphate kinase (Ndk). The human orthologue of Ndk is the NM23 metastasis suppressor, which we found to exhibit a similar activity. Purified Ndk effectively inactivates several of the oncogenic forms of Ras that are seen frequently in human cancers, including RasD12, the most commonly detected Ras mutation. Significantly, Ndk does not detectably affect wild-type Ras or an activated form of the Ras-related Rho GTPase. These results demonstrate that it is possible, through biochemical means, to specifically inactivate oncogenic Ras as a potential therapeutic approach to tumors that harbor Ras mutations. Moreover, the results suggest that the loss of NM23 expression that is commonly observed during tumor progression could lead to increased potency of oncogenic Ras proteins.
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PMID:Specific biochemical inactivation of oncogenic Ras proteins by nucleoside diphosphate kinase. 1287 11

Ca2+ sensitivity of smooth muscle and nonmuscle myosin II reflects the ratio of activities of myosin light-chain kinase (MLCK) to myosin light-chain phosphatase (MLCP) and is a major, regulated determinant of numerous cellular processes. We conclude that the majority of phenotypes attributed to the monomeric G protein RhoA and mediated by its effector, Rho-kinase (ROK), reflect Ca2+ sensitization: inhibition of myosin II dephosphorylation in the presence of basal (Ca2+ dependent or independent) or increased MLCK activity. We outline the pathway from receptors through trimeric G proteins (Galphaq, Galpha12, Galpha13) to activation, by guanine nucleotide exchange factors (GEFs), from GDP. RhoA. GDI to GTP. RhoA and hence to ROK through a mechanism involving association of GEF, RhoA, and ROK in multimolecular complexes at the lipid cell membrane. Specific domains of GEFs interact with trimeric G proteins, and some GEFs are activated by Tyr kinases whose inhibition can inhibit Rho signaling. Inhibition of MLCP, directly by ROK or by phosphorylation of the phosphatase inhibitor CPI-17, increases phosphorylation of the myosin II regulatory light chain and thus the activity of smooth muscle and nonmuscle actomyosin ATPase and motility. We summarize relevant effects of p21-activated kinase, LIM-kinase, and focal adhesion kinase. Mechanisms of Ca2+ desensitization are outlined with emphasis on the antagonism between cGMP-activated kinase and the RhoA/ROK pathway. We suggest that the RhoA/ROK pathway is constitutively active in a number of organs under physiological conditions; its aberrations play major roles in several disease states, particularly impacting on Ca2+ sensitization of smooth muscle in hypertension and possibly asthma and on cancer neoangiogenesis and cancer progression. It is a potentially important therapeutic target and a subject for translational research.
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PMID:Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. 1450 7

Elevated expression of fucosylated glycoconjugates and fucosyltransferases (Fuc-Ts) is found in various tumor cells and has been correlated with aspects of tumor progression such as cell adhesion and metastasis. Thus, fucosyltransferase inhibitors are potentially useful as anti-tumor agents. In the present study, three known spirocyclic drimanes (1, 2, and 3) were isolated from the culture broth of the fungus Stachybotrys cylindrospora. Compound 1 (stachybotrydial) exhibits potent inhibitory activity against alpha1,3-fucosyltransferase (Fuc-TV) during screening, while compounds 2 and 3 show no such inhibitory activity. Kinetic analysis indicates that compound 1 is an uncompetitive inhibitor with respect to GDP-fucose and a noncompetitive inhibitor with respect to N-acetyllactosamine with Ki values of 10.7 and 9.7 microM, respectively. In addition, all three compounds also possess inhibitory activity against sialyltransferase (ST) but not against beta1,4-galactosyltransferase. These observations provide novel chemical structure information that will help in the design of novel Fuc-T and ST inhibitors.
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PMID:Stachybotrydial, a potent inhibitor of fucosyltransferase and sialyltransferase. 1588 70

The Rho GDP dissociation inhibitors (RhoGDIs) are a major class of regulators of Rho GTPases and play essential roles in normal cell growth and malignant transformation. Although RhoGDIs are known to inhibit Rho activities, recent studies indicate that RhoGDIs can also act as positive regulators through their ability to target Rho GTPases to specific subcellular membranes or to protect the GTPases from degradation by caspases. RhoGDIs are aberrantly expressed in human tumors and this may contribute to Rho-induced cancer progression. This review will discuss the dual roles of RhoGDIs in the regulation of Rho GTPases, highlighting a possible role in regulating tumorigenicity. In addition, the potential for targeting RhoGDIs for anticancer therapy will be discussed.
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PMID:Rho GDP dissociation inhibitors as potential targets for anticancer treatment. 1680 67

Most deaths from urinary bladder cancer are owing to metastatic disease. A reduction in Rho GDP Dissociation Inhibitor 2 (RhoGDI2) protein has been associated with increased risk of metastasis in patients with locally advanced bladder cancer, whereas in animal models, RhoGDI2 reconstitution in cells without expression results in lung metastasis suppression. Recently, we noted an inverse correlation between tumor RhoGDI2 and Neuromedin U (NMU) expression, suggesting that NMU might be a target of the lung metastasis suppressor effect of RhoGDI2. Here we evaluated whether NMU is regulated by RhoGDI2 and is functionally important in tumor progression. We used small interfering RNA knockdown of endogenous RhoGDI2 in poorly tumorigenic and non-metastatic human bladder cancer T24 cells and observed increased NMU RNA expression. Although NMU overexpression did not increase the monolayer growth of T24 or related T24T poorly metastatic human bladder cancer cells, it did augment anchorage-independent growth for the latter. Overexpression of NMU in T24 and T24T cells significantly promoted tumor formation of both cell lines in nude mice, but did not alter the growth rate of established tumors. Furthermore, NMU-overexpressing xenografts were associated with lower animal body weight than control tumors, indicating a possible role of NMU in cancer cachexia. NMU overexpression in T24T cells significantly enhanced their lung metastatic ability. Bioluminescent in vivo imaging revealed that lung metastases in T24T grew faster than the same tumors in the subcutaneous microenvironment. In conclusion, NMU is a RhoGDI2-regulated gene that appears important for tumorigenicity, lung metastasis and cancer cachexia, and thus a promising therapeutic target in cancer.
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PMID:Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia. 1687 52

Invasion and metastasis are the critical steps in cancer progression that lead to death from this disease. Intense investigation into the underlying mechanisms of metastasis has revealed a complex set of signaling pathways that regulate the process. Since the mid-1980s, it has been demonstrated that the Rho family of proteins plays a major role in these pathways. Proteins that regulate Rho, including guanine nucleotide exchange factors, GTPase-activating proteins, and Rho GDP dissociation inhibitors (RhoGDIs), have also been shown to contribute to cancer progression. Among this group of Rho-regulating proteins is RhoGDI2 (RhoGDIbeta/LyGDI/GDID4/RabGDIbeta). Our laboratory initially identified RhoGDI2 as a metastasis suppressor due to its differential expression between metastatically capable and poorly metastatic bladder cancer cell lines. Over the subsequent years, in vivo and in vitro systems have been used to model steps in the metastatic cascade and to test how the expression of RhoGDI2 affected those processes. This chapter describes several of the more significant methods used to investigate the role of RhoGDI2 in bladder cancer invasion and metastasis. These methods include an in vitro assay for invasion using bladder organ cultures, lung metastasis assays in immunocompromised murine hosts, polymerase chain reaction-based quantification of metastatic burden, and derivation of increasingly metastatic cell lines.
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PMID:Invasion and metastasis models for studying RhoGDI2 in bladder cancer. 1837 68

The Rho family GTPase Cdc42 regulates cytoskeletal organization and membrane trafficking in physiological processes such as cell proliferation, motility and polarity. Aberrant activation of Cdc42 results in pathogenesis, such as tumorigenesis and tumor progression, cardiovascular diseases, diabetes, and neuronal degenerative diseases. The activation of Cdc42 in response to upstream signals is mediated by guanine nucleotide exchange factors (GEFs), which converse GDP-bound inactive form to the GTP-bound active form of Cdc42. The activated Cdc42 transduces signals to downstream effectors and generates cellular effects. This review will discuss the molecular mechanism of activation of Cdc42 and postulate that signaling specificity of Cdc42 is conferred by the GEF/GTPase/Effector (GGE) complexes in response to external stimuli.
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PMID:Cellular signaling for activation of Rho GTPase Cdc42. 1855 78

The GDP dissociation inhibitors (GDIs) are pivotal regulators of Rho GTPases, which are essential for tumor progression, particularly in the area of metastasis. One member of GDIs was identified as RhoGDI (Rho GDP-dissociation inhibitor alpha, or RhoGDIalpha), but little is known about this protein in tumors. In this study, we used comparative proteomic analysis to show that RhoGDI is markedly up-regulated in metastatic colorectal cancer (CRC). The elevated level of RhoGDI protein in metastatic CRC was confirmed by Western blot at the tissue ( n = 24) and cell ( n = 6) levels. Further, we analyzed RhoGDI protein expression in 126 clinicopathologically characterized CRC cases by immunohistochemistry. Statistical analysis showed that there were significant differences of RhoGDI overexpression in patients categorized according to tumor invasion ( p = 0.018), lymph node metastasis ( p = 0.001) and clinical stage ( p = 0.009). A trend was also identified between high expression of RhoGDI and shorter overall survival ( p = 0.013). In the present work, we also analyzed the effect of RhoGDI on CRC cell line. Gene transfection-mediated overexpression of RhoGDI in HT29 cells, containing a low detectable level of endogenous RhoGDI, resulted in a significant increase in cell proliferation and motility in vitro. These data suggest that RhoGDI may promote CRC progression and metastasis by stimulating tumor cell growth and migration.
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PMID:Overexpression of Rho GDP-dissociation inhibitor alpha is associated with tumor progression and poor prognosis of colorectal cancer. 1865 61

Rho GDP-Dissociation Inhibitors (RhoGDIs) are important regulators of the Rho family of small GTPases. The expression of RhoGDIs is altered in a variety of cancers and they have been shown to mediate several processes during tumorigenesis and cancer progression. Using examples of RhoGDI-mediated signaling and expression patterns in endothelial cells as well as pancreatic, breast, and bladder cancer, the multitude of potential cancer therapeutic targets presented by a better understanding of their function is illustrated. Several novel therapeutic strategies are proposed for intervening in RhoGDI signaling, and potential complications arising from their implementation are discussed.
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PMID:RhoGDI signaling provides targets for cancer therapy. 2034 89


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