Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human CD3AK and LAK cells were prepared from peripheral blood mononuclear cells (PBMC) by culturing them in recombinant IL-2 (rIL-2, 30 mu/ml) and anti-CD3 monoclonal antibody, and in rIL-2 alone (300/ml), respectively. By MTT assay, it was found that the PBMC, when cultured in the presence of anti-CD3/rIL-2, proliferated more actively and persistently than PBMC cultured in the presence of rIL-2 alone. In vitro cytotoxicity assay showed that CD3AK cells had stronger killing activity against a poorly differentiated human gastric adenocarcinoma cell line MNK 45 than LAK cells did. Winn's assay at an E/T ratio of 20 carried out in nude mice also indicated that CD3AK cells were more effective than LAK cells in tumor growth inhibition. When the nude mice were inoculated with MNK 45 admixed with CD3AK, none of them developed tumor whereas those inoculated with either MNK 45 or MNK 45 admixed with LAK cells all developed tumor. The results indicate that CD3AK would be a better choice than LAK for the adoptive immunotherapy of human stomach cancer.
 ...
PMID:[Experimental study of the anti-tumor activity of CD3AK against human gastric cancer cell line in vitro and in vivo]. 792 59

Little is known about the mechanism by which lymphokine-activated killer (LAK) cells and natural killer (NK) cells recognize and lyse target cells. We undertook this study to investigate the effects of target cell membrane modification by sodium periodate (PI) on the lysis of tumor cells by human and murine LAK cells (HLAK, MLAK) and NK cells (HNK, MNK). LAK and NK cells were generated and used as effector cells in 4-hr 51Cr release assays against a variety of PI-treated and untreated target cells. PI significantly increased the MLAK cell-mediated lysis of YAC and MH134 tumor cells, but had no effect on the MNK lysis of YAC or MH134 tumor cells. PI had no effect on the HLAK or HNK lysis of YAC or MH134 tumor cells. PI had no effect on the MLAK or MNK lysis of K562 or U937 human tumor cells. Similarly, PI had no effect on the HLAK lysis of K562, but did significantly increase the HNK lysis of K562. PI increased both the HLAK and HNK lysis of U937. Cold target inhibition studies revealed that PI-treated YAC cells inhibited the MLAK cell-mediated lysis of untreated YAC cells. The variable effects of PI on LAK cell- and NK cell-mediated lysis support the hypothesis that LAK cells are a distinct population of cells rather than a subpopulation of NK cells on the basis of mechanism of target cell recognition. The results of the cold target inhibition study suggest that PI-treated tumor cells are identified by effector cells in a manner similar to that of untreated cells.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Target cell membrane modification and susceptibility to lymphokine-activated killer cell-mediated lysis. II. Sodium periodate has a differential effect on the lysis of human and murine tumor cells. 812 Nov 71

Copper is a tightly regulated trace element. Disruptions of copper homeostasis are rare and they cause serious disorders such as Wilson's disease and Menkes disease. Copper also plays an important role in promoting physiological and malignant angiogenesis. Formation of new blood vessels by a tumor enables tumor growth, invasion and metastasis. The copper chelator tetrathiomolybdate (TM), which quickly and effectively depletes copper stores, is under investigation as an anti-angiogenic agent. Promising results in vitro, in pre-clinical animal models and in an early (phase I) clinical trial have led to ongoing phase II evaluation of TM in patients with advanced cancers.
 ...
PMID:Copper deficiency as an anti-cancer strategy. 1516 1

Satraplatin is an orally bioavailable platinum analog that has activity in prostate cancer. JM118 is the most abundant species found in the plasma following the oral ingestion of satraplatin and has anti-tumor activity in vitro against cell lines that are resistant to cisplatin (DDP). The goal of the current study was to determine whether the activity of JM118 in some DDP-resistant cells can be explained by differences in the cellular pharmacology of the two drugs. The effect of each of the Cu transporters CTR1, ATP7A and ATP7B on sensitivity to the growth inhibitory effect of JM118 and its cellular pharmacology was examined to identify the characteristics of JM118 that distinguish it from DDP. These studies were performed using wild type and CTR1-/- homozygous knockout mouse embryo cells, and human Me32a Menkes disease fibroblasts that do not express either ATP7A or ATP7B plus sublines molecularly engineered to express either ATP7A (MeMNK cells) or ATP7B (MeWND cells). Knockout of the Cu influx transporter CTR1 in murine embryo cells increased their resistance to DDP and reduced its cellular accumulation but had no effect on sensitivity to JM118 or its uptake. In the case of DDP, forced expression of either of the two Cu efflux transporters, ATP7A or ATP7B, in Me32a cells rendered them resistant to DDP, increased whole cell accumulation of Pt but reduced the amount of Pt in DNA. In the case of JM118, forced expression of either ATP7A or ATP7B rendered Me32a cells resistant, increased not only whole cell Pt accumulation but also increased rather than decreased the amount of Pt in DNA. These results demonstrate that both ATP7A and ATP7B mediate resistance to JM118 as well as DDP and suggest that they sequester both DDP and JM118 into vesicular compartments within the cell resulting in enhanced whole cell accumulation and reduced cytotoxicity. We conclude that there are two important differences between DDP and JM118 with respect to the effect of Cu transporters on their cellular pharmacology. First, whereas CTR1 is involved in DDP accumulation it does not play a role in the uptake of JM118. Second, ATP7A and ATP7B, while they both mediate resistance, have opposite effects on the accumulation of Pt in DNA following exposure to the two drugs. ATP7A and ATP7B appear to be able to modulate the toxicity of the Pt that accumulates in DNA following exposure to JM118. These results suggest that JM118 will retain activity in cells in which DDP resistance is due to the loss of CTR1, but not in cells in which resistance is due to enhanced expression of ATP7A or ATP7B.
 ...
PMID:Modulation of the cellular pharmacology of JM118, the major metabolite of satraplatin, by copper influx and efflux transporters. 1617 May 71

Genetically engineered mouse models are powerful tools for studying cancer genes and validating targets for cancer therapy. We previously used a mouse lymphoma model to demonstrate that the translation initiation factor eIF4E is a potent oncogene in vivo. Using the same model, we now show that the oncogenic activity of eIF4E correlates with its ability to activate translation and become phosphorylated on Ser 209. Furthermore, constitutively activated MNK1, an eIF4E Ser 209 kinase, promotes tumorigenesis in a manner similar to eIF4E, and a dominant-negative MNK mutant inhibits the in vivo proliferation of tumor cells driven by mutations that deregulate translation. Phosphorylated eIF4E promotes tumorigenesis primarily by suppressing apoptosis and, accordingly, the anti-apoptotic protein Mcl-1 is one target of both phospho-eIF4E and MNK1 that contributes to tumor formation. Our results provide insight into how eIF4E contributes to tumorigenesis and pinpoint a level of translational control that may be suitable for therapeutic intervention.
 ...
PMID:Dissecting eIF4E action in tumorigenesis. 1805 95

Deregulation of the phosphatidyl inositol trisphosphate kinase/AKT/mammalian target of rapamycin (mTOR) and RAS/mitogen-activated protein kinase (MAPK)/MNK pathways frequently occurs in human prostate carcinomas (PCas) and leads to aberrant modulation of messenger RNA (mRNA) translation. We have investigated the relative contribution of these pathways to translational regulation and proliferation of PCa cells. MNK-dependent phosphorylation of eIF4E is elevated in DU145 cells, which have low basal levels of AKT/mTOR activity due to the expression of the tumor suppressor PTEN. In contrast, eIF4E phosphorylation is low in PC3 and LNCaP cells with mutated PTEN and constitutively active AKT/mTOR pathway, but it can be strongly induced through inhibition of mTOR activity by rapamycin or serum depletion. Remarkably, we found that inhibition of MNKs strongly reduced the polysomal recruitment of terminal oligopyrimidine messenger RNAs (TOP mRNAs), which are known targets of mTOR-dependent translational control. Pull-down assays of the eIF4F complex indicated that translation initiation was differently affected by inhibition of MNKs and mTOR. In addition, concomitant treatment with MNK inhibitor and rapamycin exerted additive effects on polysomal recruitment of TOP mRNAs and protein synthesis. The MNK inhibitor was more effective than rapamycin in blocking proliferation of PTEN-expressing cells, whereas combination of the two inhibitors suppressed cell cycle progression in both cell lines. Microarray analysis showed that MNK affected translation of mRNAs involved in cell cycle progression. Thus, our results indicate that a balance between the activity of the AKT/mTOR and the MAPK/MNK pathway in PCa cells maintains a defined translational level of specific mRNAs required for ribosome biogenesis, cell proliferation and stress response and might confer to these cells the ability to overcome negative insults.
 ...
PMID:Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells. 1880 72

Copper is an essential trace element and several copper containing proteins are indispensable for such processes as oxidative respiration, neural development and collagen remodeling. Copper metabolism is precisely regulated by several transporters and chaperone proteins. Copper Transport Protein 1 (CTR1) selectively uptakes copper into cells. Subsequently three chaperone proteins, HAH1 (human atx1 homologue 1), Cox17p and CCS (copper chaperone for superoxide dismutase) transport copper to the Golgi apparatus, mitochondria and copper/zinc superoxide dismutase respectively. Defects in the copper transporters ATP7A and ATP7B are responsible for Menkes disease and Wilson's disease respectively. These proteins transport copper via HAH1 to the Golgi apparatus to deliver copper to cuproenzymes. They also prevent cellular damage from an excess accumulation of copper by mediating the efflux of copper from the cell. There is increasing evidence that copper transport mechanisms may play a role in drug resistance. We, and others, found that ATP7A and ATP7B are involved in drug resistance against the anti-tumor drug cis-diamminedichloroplatinum (II) (CDDP). A relationship between the expression of ATP7A or ATP7B in tumors and CDDP resistance is supported by clinical studies. In addition, the copper uptake transporter CTR1 has also been reported to play a role in CDDP sensitivity. Furthermore, we have recently found that the effect of ATP7A on drug resistance is not limited to CDDP. Using an ex vivo drug sensitivity assay, the histoculture drug response assay (HDRA), the expression of ATP7A in human surgically resected colon cancer cells correlated with sensitivity to 7-ethyl-10-hydroxy-camptothecin (SN-38). ATP7A-overexpressing cells are resistant to many anticancer drugs including SN-38, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11), vincristine, paclitaxel, etoposide, doxorubicin (Dox), and mitoxantron. The mechanism by which ATP7A and copper metabolism modulate drug transport appears to involve modulation of drug cellular localization via modulation of the vesicle transport system. In ATP7A overexpressing cells, Dox accumulates in the Golgi apparatus. In contrast, in the parental cells, Dox is localized in the nuclei, where the target molecules of Dox, topoisomerase II and DNA, are found. Disruption of the intracellular vesicle transport system with monensin, a Na+/H+ ionophore, induced the relocalization of Dox from the Golgi apparatus to the nuclei in the ATP7A overexpressing cells. These data suggested that ATP7A-related drug transport is dependent on the vesicle transport system. Thus copper transport systems play important roles in drug transport as well as in copper metabolism. Components of copper metabolism are therefore likely to include target molecules for the modulation of drug potency of not only anti-cancer agents but also of other drugs.
 ...
PMID:Copper transport systems are involved in multidrug resistance and drug transport. 1907 68

Activation of the translation initiation factor 4E (eIF4E) promotes malignant transformation and metastasis. Signaling through the AKT-mTOR pathway activates eIF4E by phosphorylating the inhibitory 4E binding proteins (4E-BP). This liberates eIF4E and allows binding to eIF4G. eIF4E can then be phosphorylated at serine 209 by the MAPK-interacting kinases (Mnk), which also interact with eIF4G. Although dispensable for normal development, Mnk function and eIF4E phosphorylation promote cellular proliferation and survival and are critical for malignant transformation. Accordingly, Mnk inhibition may serve as an attractive cancer therapy. We now report the identification of a potent, selective and orally bioavailable Mnk inhibitor that effectively blocks 4E phosphorylation both in vitro and in vivo. In cultured cancer cell lines, Mnk inhibitor treatment induces apoptosis and suppresses proliferation and soft agar colonization. Importantly, a single, orally administered dose of this Mnk inhibitor substantially suppresses eIF4E phosphorylation for at least 4 hours in human xenograft tumor tissue and mouse liver tissue. Moreover, oral dosing with the Mnk inhibitor significantly suppresses outgrowth of experimental B16 melanoma pulmonary metastases as well as growth of subcutaneous HCT116 colon carcinoma xenograft tumors, without affecting body weight. These findings offer the first description of a novel, orally bioavailable MNK inhibitor and the first preclinical proof-of-concept that MNK inhibition may provide a tractable cancer therapeutic approach.
 ...
PMID:Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases. 2123 35

When mTOR inhibitor rapalogs prevent cap-dependent translation of cell-cycle proteins like c-myc, continuing tumor cell growth depends on cap-independent translation, which is mediated by internal ribosome entry sites (IRESes) located in the 5'-UTR (untranslated region) of transcripts. To investigate if rapalog-induced activation of MNK kinases had a role in such IRES activity, we studied multiple myeloma (MM) cells. Rapamycin (RAP)-activated MNK1 kinase activity in MM cell lines and primary specimens by a mitogen-activated protein kinase-dependent mechanism. Pharmacological inhibition of MNK activity or genetic silencing of MNK1 prevented a rapalog-induced upregulation of c-myc IRES activity. Although RAP, used alone, had little effect on myc protein expression, when combined with a MNK inhibitor, myc protein expression was abrogated. In contrast, there was no inhibition of myc RNA, consistent with an effect on myc translation. In a RAP-resistant MM cell lines as well as a resistant primary MM specimen, co-exposure to a MNK inhibitor or MNK1 knockdown significantly sensitized cells for RAP-induced cytoreduction. Studies in MNK-null murine embryonic fibroblasts additionally supported a role for MNK kinases in RAP-induced myc IRES stimulation. These results indicate that MNK kinase activity has a critical role in the fail-safe mechanism of IRES-dependent translation when mTOR is inhibited. As kinase activity also regulated sensitivity to RAP, the data also provide a rationale for therapeutically targeting MNK kinases for combined treatment with mTOR inhibitors.
 ...
PMID:MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells. 2237 Jun 34

Gastric cancer is the second leading cause of cancer mortality, but the molecular mechanisms underlying its progression and metastasis remain unclear. CCR7 and Dicer 1 protein expression in 80 gastric adenocarcinomas and 40 peritumoral tissues were measured by immunohistochemical staining. The expression of let-7a miRNA in serum, tumor tissues, and peritumoral tissues was measured by real-time PCR. The role of let-7a in CCR7 protein expression, migration, and invasion of gastric cancer cells was tested in vitro. Dicer 1 protein expression was found to be significantly reduced, whereas CCR7 protein expression was significantly increased in gastric adenocarcinomas compared to peritumoral tissues. The let-7a miRNA levels in the serum and tumor tissues of gastric adenocarcinoma patients were significantly lower than in the serum of healthy controls and peritumoral tissues, respectively. Dicer 1 protein positively correlated with let-7a miRNA level, but negatively correlated with CCR7 protein level in gastric adenocarcinoma. Negative Dicer 1 protein and let-7a miRNA expression and positive CCR7 protein expression significantly correlated with lymph node metastasis, depth of invasion, high clinical TNM stage, and larger tumor size. Let-7a transfection significantly inhibited CCR7 protein expression, migration, and invasion of MNK-45 cells in vitro. High expression of CCR7 protein and low expression of Dicer 1 protein and let-7a miRNA are significantly associated with the metastasis and progression of gastric cancer. High CCR7 protein expression may be caused by the loss of Dicer 1 protein expression and reduced let-7a miRNA level in gastric cancer. The serum let-7a level might be a marker for the diagnosis of gastric cancer.
Tumour Biol 2013 Jun
PMID:The regulatory mechanism of CCR7 gene expression and its involvement in the metastasis and progression of gastric cancer. 2351 40


1 2 3 Next >>