UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ras proteins function as molecular switches that cycle between an inactive GDP-bound state, and an active GTP-bound form that triggers different signaling pathways. Because Ras can integrate both proliferative and anti-apoptotic stimuli, GTP-locked Ras mutants play a critical role in the development of human tumors. Moreover, wild-type Ras relays the transforming potential of a number of molecules involved in tumor development, including protein tyrosine kinases. Consequently, the molecular intermediates that control Ras activation are potential targets of anti-tumoral pharmacology. Besides the canonical Shc/Grb2/Sos module classically involved in Ras activation, novel effectors have recently been shown to participate in this pathway, including the multivalent Grb2-associated docking protein Gab1, the protein tyrosine phosphatase SHP-2, and the phosphoinositide 3-kinase. Recent genetic advances have shown that these proteins are critically involved in cell proliferation and survival, further suggesting that they could be interesting targets for selective tumor therapy. Here we review recent progress in our understanding of the role of Gab1 and its partners in Ras activation, and other survival/proliferation pathways. Implications for the pharmacological manipulation of this pathway in the treatment of cancer will also be discussed.
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PMID:Gab1, SHP-2 and other novel regulators of Ras: targets for anticancer drug discovery? 1276 87

PTEN is a tumor suppressor that reverses the action of phosphoinositide 3-kinase by catalyzing the removal of the 3' phosphate of phosphoinositides. Despite the critical role of PTEN in cell signaling and regulation, the mechanisms of its membrane recruitment and activation is still poorly understood. PTEN is composed of an N-terminal phosphatase domain, a C2 domain, and a C-terminal tail region that contains the PSD-95/Dlg/ZO-1 homology (PDZ) domain-binding sequence and multiple phosphorylation sites. Our in vitro surface plasmon resonance measurements using immobilized vesicles showed that both the phosphatase domain and the C2 domain, but not the C-terminal tail, are involved in electrostatic membrane binding of PTEN. Furthermore, the phosphorylation-mimicking mutation on the C-terminal tail of PTEN caused an approximately 80-fold reduction in its membrane affinity, mainly by slowing the membrane-association step. Subcellular localization studies of PTEN transfected into HEK293T and HeLa cells indicated that targeting of PTEN to the plasma membrane is coupled with rapid degradation and that the phosphatase domain and the C2 domain are both necessary and sufficient for its membrane recruitment. Results also indicated that the phosphorylation regulates the targeting of PTEN to the plasma membrane not by blocking the PDZ domain-binding site but by interfering with electrostatic membrane binding of PTEN. On the basis of these results, we propose a membrane-binding and activation mechanism for PTEN, in which the phosphorylation/dephosphorylation of the C-terminal region serves as an electrostatic switch that controls the membrane translocation of the protein.
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PMID:Membrane-binding and activation mechanism of PTEN. 1280 47

Lysophosphatidic acid (LPA) is a bioactive molecule involved in inflammation, immunity, wound healing, and neoplasia. Its pleiotropic actions arise presumably by interaction with their cell surface G protein-coupled receptors. Herein, the presence of the specific nuclear lysophosphatidic acid receptor-1 (LPA1R) was revealed in unstimulated porcine cerebral microvascular endothelial cells (pCMVECs), LPA1R stably transfected HTC4 rat hepatoma cells, and rat liver tissue using complementary approaches, including radioligand binding experiments, electron- and cryomicroscopy, cell fractionation, and immunoblotting with three distinct antibodies. Coimmunoprecipitation studies in enriched plasmalemmal fractions of unstimulated pCMVEC showed that LPA1Rs are dually sequestrated in caveolin-1 and clathrin subcompartments, whereas in nuclear fractions LPA1R appeared primarily in caveolae. Immunofluorescent assays using a cell-free isolated nuclear system confirmed LPA1R and caveolin-1 co-localization. In pCMVEC, LPA-stimulated increases in cyclooxygenase-2 and inducible nitric-oxide synthase RNA and protein expression were insensitive to caveolea-disrupting agents but sensitive to LPA-generating phospholipase A2 enzyme and tyrosine kinase inhibitors. Moreover, LPA-induced increases in Ca2+ transients and/or iNOS expression in highly purified rat liver nuclei were prevented by pertussis toxin, phosphoinositide 3-kinase/Akt inhibitor wortmannin and Ca2+ chelator and channel blockers EGTA and SK&F96365, respectively. This study describes for the first time the nucleus as a potential organelle for LPA intracrine signaling in the regulation of pro-inflammatory gene expression.
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PMID:Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1. 1284 11

The tuberous sclerosis complex (TSC) is a genetic disorder that is caused through mutations in either one of the two tumor suppressor genes, TSC1 and TSC2, that encode hamartin and tuberin, respectively. Interaction of hamartin with tuberin forms a heterodimer that inhibits signaling by the mammalian target of rapamycin to its downstream targets: eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). During mitogenic sufficiency, the phosphoinositide 3-kinase (PI3K)/Akt pathway phosphorylates tuberin on Ser-939 and Thr-1462 that inhibits the tumor suppressor function of the TSC complex. Here we show that tuberin-hamartin heterodimers block protein kinase C (PKC)/MAPK- and phosphatidic acid-mediated signaling toward mammalian target of rapamycin-dependent targets. We also show that two TSC2 mutants derived from TSC patients are defective in repressing phorbol 12-myristate 13-acetate-induced 4E-BP1 phosphorylation. PKC/MAPK signaling leads to phosphorylation of tuberin at sites that overlap with and are distinct from Akt phosphorylation sites. Phosphorylation of tuberin by phorbol 12-myristate 13-acetate was reduced by treatment of cells with either bisindolylmaleimide I or UO126, inhibitors of PKC and MAPK/MEK (MAPK/ERK kinase), respectively, but not by wortmannin (an inhibitor of PI3K). This work reveals that both PI3K-independent and -dependent mechanisms modulate tuberin phosphorylation in vivo.
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PMID:Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and -independent phosphorylation of tuberin. 1286 26

Because the aberrantly activated phosphoinositide 3-kinase (PI3K)/Akt pathway renders tumor cells resistant to cytotoxic insults, including those related to anticancer drugs, inhibition of the pathway may possibly restore or augment the effectiveness of chemotherapy. Using the human malignant glioma cell lines U87, A172, LN18, and LN229, we examined effects of the PI3K inhibitor LY294002 on both apoptosis and cytotoxicity induced by chemotherapeutic agents, including antimicrotubule agents vincristine and paclitaxel, an alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea, a topoisomerase II inhibitor etoposide, and a DNA cross-linking agent cisplatin (cis-diamminedichloroplatinum), and we compared the LY294002-induced enhancement of effects of those agents. Ten to 20 micro M LY294002 augmented both apoptosis and caspase 3-like activity caused by antimicrotubule agents to a larger extent than induced by 1,3-bis(2-chloroethyl)-1-nitrosourea, etoposide, and cisplatin in all four malignant glioma cell lines examined. The same doses of LY294002 enhanced cytotoxicity more efficiently with antimicrotubule agents than with other chemotherapeutic agents. Quantitative analyses using a modified isobologram and median effect plot method revealed that enhancement by LY294002 of vincristine- or paclitaxel-induced cytotoxicity was synergistic, whereas enhancement by the PI3K inhibitor of the other chemotherapeutic agent-induced cytotoxicity was additive. Our study indicates that the synergistic augmentation of the cytotoxicity by LY294002 occurs specifically with antimicrotubule agents, at least partially through an increase in caspase 3-dependent apoptosis, and we suggest that inhibitors of the PI3K/Akt pathway in combination with antimicrotubule agents may induce cell death effectively and be a potent modality to treat patients with malignant gliomas.
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PMID:Synergistic augmentation of antimicrotubule agent-induced cytotoxicity by a phosphoinositide 3-kinase inhibitor in human malignant glioma cells. 1287 4

Lymphocyte homeostasis is regulated by mechanisms that control lymphocyte proliferation and apoptosis. Activation-induced cell death is mediated by the expression of death ligands and receptors, which, when triggered, activate an apoptotic cascade. Bovine T cells transformed by the intracellular parasite Theileria parva proliferate in an uncontrolled manner and undergo clonal expansion. They constitutively express the death receptor Fas and its ligand, FasL but do not undergo apoptosis. Upon elimination of the parasite from the host cell by treatment with a theilericidal drug, cells become increasingly sensitive to Fas/FasL-induced apoptosis. In normal T cells, the sensitivity to death receptor killing is regulated by specific inhibitor proteins. We found that anti-apoptotic proteins such as cellular (c)-FLIP, which functions as a catalytically inactive form of caspase-8, and X-chromosome-linked inhibitor of apoptosis protein (IAP) as well as c-IAP, which can block downstream executioner caspases, are constitutively expressed in T. parva-transformed T cells. Expression of these proteins is rapidly down-regulated upon parasite elimination. Antiapoptotic proteins of the Bcl-2 family such as Bcl-2 and Bcl-x(L) are also expressed but, in contrast to c-FLIP, c-IAP, and X-chromosome-linked IAP, do not appear to be tightly regulated by the presence of the parasite. Finally, we show that, in contrast to the situation in tumor cells, the phosphoinositide 3-kinase/Akt pathway is not essential for c-FLIP expression. Our findings indicate that by inducing the expression of antiapoptotic proteins, T. parva allows the host cell to escape destruction by homeostatic mechanisms that would normally be activated to limit the continuous expansion of a T cell population.
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PMID:Theileria parva-transformed T cells show enhanced resistance to Fas/Fas ligand-induced apoptosis. 1287 9

Vasculogenic mimicry (VM) describes the unique ability of highly aggressive melanoma tumor cells to express endothelial cell-associated genes (such as EphA2 and VE-cadherin) and form vasculogenic-like networks when cultured on a three-dimensional matrix. VM has been described in several types of aggressive tumors, including melanoma, prostate, breast, and ovarian carcinomas. However, the molecular underpinnings of this phenomenon remain somewhat elusive. In this study, we examined key molecular mechanisms underlying VM in aggressive human cutaneous and uveal melanoma. The data reveal that phosphoinositide 3-kinase (PI3K) is an important regulator of VM, specifically affecting membrane type 1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2) activity, critical in the formation of vasculogenic-like networks. Using specific inhibitors of PI3K, melanoma VM was abrogated coincident with decreased MMP-2 and MT1-MMP activity. Furthermore, inhibition of PI3K blocked the cleavage of laminin 5 gamma 2 chain, resulting in decreased levels of the gamma 2' and gamma 2x promigratory fragments. Collectively, these results indicate that PI3K is an important regulator of melanoma VM directly affecting the cooperative interactions of MMP-2, MT1-MMP, and laminin 5 gamma 2 chain and, thus, the remodeling of the tumor cell microenvironment. PI3K may represent an excellent target for therapeutic intervention of a novel signaling cascade underlying VM.
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PMID:Phosphoinositide 3-kinase regulates membrane Type 1-matrix metalloproteinase (MMP) and MMP-2 activity during melanoma cell vasculogenic mimicry. 1294 89

During carcinoma progression, tumor cells often undergo changes similar (but not identical) to epithelialmesenchymal transitions in embryonic development. In this study, we demonstrate that experimental stimulation of hyaluronan synthesis in normal epithelial cells is sufficient to induce mesenchymal and transformed characteristics. Using recombinant adenoviral expression of hyaluronan synthase-2, we show that increased hyaluronan production promotes anchorage-independent growth and invasiveness, induces gelatinase production, and stimulates phosphoinositide 3-kinase/Akt pathway activity in phenotypically normal Madin-Darby canine kidney and MCF-10A human mammary epithelial cells. Cells infected with hyaluronan synthase-2 adenovirus also acquired mesenchymal characteristics, including up-regulation of vimentin, dispersion of cytokeratin, and loss of organized adhesion proteins at intercellular boundaries. Furthermore, we show that the transforming effects of two well described agents, hepatocyte growth factor (HGF) and beta-catenin, are dependent on hyaluronan-cell interactions. Perturbation of endogenous hyaluronan polymer interactions by treatment with hyaluronan oligomers is shown here to reverse the transforming effects of HGF and beta-catenin in Madin-Darby canine kidney and MCF-10A human mammary epithelial cells. Also, HGF and beta-catenin induced assembly of hyaluronan-dependent pericellular matrices similar to those surrounding mesenchymal cells. Thus, increased expression of hyaluronan is sufficient to induce epithelial-mesenchymal transition and acquisition of transformed properties in phenotypically normal epithelial cells.
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PMID:Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells. 1295 18

It is now well established that the reduced capacity of tumor cells of undergoing cell death through apoptosis plays a key role both in the pathogenesis of cancer and in therapeutic treatment failure. Indeed, tumor cells frequently display multiple alterations in signal transduction pathways leading to either cell survival or apoptosis. In mammals, the pathway based on phosphoinositide 3-kinase (PI3K)/Akt conveys survival signals of extreme importance and its downregulation, by means of pharmacological inhibitors of PI3K, considerably lowers resistance to various types of therapy in solid tumors. We recently described an HL60 leukemia cell clone (HL60AR cells) with a constitutively active PI3K/Akt pathway. These cells were resistant to multiple chemotherapeutic drugs, all-trans-retinoic acid (ATRA), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Treatment with two pharmacological inhibitors of PI3K, wortmannin and Ly294002, restored sensitivity of HL60AR cells to the aforementioned treatments. However, these inhibitors have some drawbacks that may severely limit or impede their clinical use. Here, we have tested whether or not a new selective Akt inhibitor, 1L-6-hydroxymethyl-chiro-inositol 2(R)-2-O-methyl-3-O-octadecylcarbonate (Akt inhibitor), was as effective as Ly294002 in lowering the sensitivity threshold of HL60 cells to chemotherapeutic drugs, TRAIL, ATRA, and ionizing radiation. Our findings demonstrate that, at a concentration which does not affect PI3K activity, the Akt inhibitor markedly reduced resistance of HL60AR cells to etoposide, cytarabine, TRAIL, ATRA, and ionizing radiation. This effect was likely achieved through downregulation of expression of antiapoptotic proteins such as c-IAP1, c-IAP2, cFLIP(L), and of Bad phosphorylation on Ser 136. The Akt inhibitor did not influence PTEN activity. At variance with Ly294002, the Akt inhibitor did not negatively affect phosphorylation of protein kinase C-zeta and it was less effective in downregulating p70S6 kinase (p70S6K) activity. The Akt inhibitor increased sensitivity to apoptotic inducers of K562 and U937, but not of MOLT-4, leukemia cells. Overall, our results indicate that selective Akt pharmacological inhibitors might be used in the future for enhancing the sensitivity of leukemia cells to therapeutic treatments that induce apoptosis or for overcoming resistance to these treatments.
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PMID:A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells. 1297 Jul 79

Glioma cells that migrate out of the main tumor mass into normal brain tissue contribute to the failure of most gliomas to respond to treatment. Treatments that target migratory glioma cells may enhance the therapeutic response. Multiple lines of evidence suggest that suppression of apoptosis accompanies activation of the migratory phenotype. Here, we determine whether migration and apoptosis are consistently linked in glioma cells and whether manipulation of migration influences cytotoxic therapy-induced apoptosis. Camptothecin and Trail-induced apoptosis were decreased 2-5-fold in actively migrating glioma cells relative to migration-restricted cells. Consistent with a mechanistic link between migration and apoptosis, the dose-response for stimulation of migration on laminin was inversely proportional to apoptosis induction. Treatment of glioma cells with migration inhibitors alone had little effect on basal rates of apoptosis and had little effect on Trail-induced or camptothecin-induced apoptosis in migration-restricted cells. By contrast, migration inhibitors increased camptothecin and Trail-induced apoptosis in actively migrating glioma cells. Migrating glioma cells have increased amounts of phosphorylated Akt and its downstream substrate glycogen synthase kinase-3 relative to migration restricted cells. Treatment of migrating cells with a specific inhibitor of phosphoinositide 3-kinase (PI3-K), LY294002, blocked the phosphorylation of Akt and increased the sensitivity to apoptosis. LY294002 had no effect on the migration of restricted cells. This suggests that migrating glioma cells activate the PI3-K survival pathway, protecting migrating cells from apoptosis. Taken together, these data provide support for a link between migration and apoptosis in glioma cells. In addition, evidence indicates that treatment with migration inhibitors, while not affecting apoptosis-induction in migration-restricted cells, can sensitize migrating glioma cells to cytotoxic agents.
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PMID:Migrating glioma cells activate the PI3-K pathway and display decreased susceptibility to apoptosis. 1313 92

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