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)

Adriamycin, a lipid-interacting anti-cancer agent, was found to inhibit the phosphorylation of polyGlu/Tyr (4:1) by tyrosine protein kinases either from spleen or expressed by the oncogene of Abelson murine leukemia virus. The dose dependent inhibition by adriamycin is accounted for by competition for the ATP binding site, but it is also deeply influenced by the nature and concentration of the phosphorylatable substrate, suggesting multiple interactions with the enzyme. The phosphorylation at tyrosine residues of cytosolic proteins from cells transformed by Abelson leukemia virus and the autophosphorylation of tyrosine protein kinases are also inhibited by adriamycin. Unlike tyrosine protein kinases most serine/threonine specific protein kinases, with the notable exception of protein kinase-C, appear to be relatively insensitive to adriamycin.
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PMID:Inhibition of tyrosine protein kinases by the antineoplastic agent adriamycin. 254 96

Two serine/threonine protein kinases were compared in C10, a clone from the nontumorigenic NAL IA cell line derived from normal mouse lung epithelium, and PCC4, a cell line derived from a mouse lung adenoma. C10 cells are contact inhibited, whereas PCC4 cells are not. Upon treatment with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), the normally flattened C10 cells round up, while the normally bipolar, rounded PCC4 cells flatten out. Three proteins of 14,000, 20,000 and 116,000 molecular weight were phosphorylated in TPA-treated particulate fractions but not in untreated particulate fractions of PCC4 cells. In contrast, TPA caused a generalized increase in the phosphorylation of most membrane proteins in C10 cells. Cytosolic protein kinase C (PKC) specific activity was lower in PCC4 cells than in C10 cells, but particulate PKC activity was similar in the two cell lines. Both measurements of PKC activity and immunoblotting assays using anti-PKC antisera showed increased particulate PKC in TPA-treated C10 cells resulting from a quantitative translocation of PKC molecules from cytoplasm to plasma membrane. This PKC response to TPA was attenuated in PCC4 cells. While PCC4 particulate PKC activity was substantially increased after TPA treatment, PKC activity decreased only slightly in cytosolic fractions of TPA-treated PCC4 cells. Immunoblots of TPA-treated PCC4 cells showed a decline in cytosolic PKC content and increased particulate PKC concentration, but these changes were not of the same magnitude as the activity changes. This may represent an unmasking of latent PKC activity since particulate PKC activity in TPA-treated PCC4 cells was inhibited by staurosporine, a specific inhibitor of PKC when used at nanomolar concentrations. In addition, PCC4 cells had less mRNA coding for the R1 regulatory subunit of cyclic AMP (cAMP)-dependent protein kinase (PKA) than C10 cells, as determined by Northern blotting using an R1 alpha cDNA probe. Consistent with this result, photolabeling with 8-azido-[32P]cAMP, a photoaffinity analog of cAMP, revealed that R1 from PCC4 cells incorporated less analogue than R1 from C10 cells. PKA-specific activity also was lower in PCC4 cells than in C10 cells. Thus, deficiencies in protein kinases which mediate the effects of diacylglycerol and cAMP second messengers were observed in neoplastic lung cells. This may dampen the responsiveness of PCC4 cells to extracellular signals that regulate cell growth and cell-cell interactions.
Cancer Res 1989 Sep 15
PMID:Altered function of protein kinase C and cyclic adenosine monophosphate-dependent protein kinase in a cell line derived from a mouse lung papillary tumor. 254 15

Several analogues of somatostatin were examined in the Mia PaCa-2 human pancreatic cancer cell line for their ability to promote tyrosine phosphatase activity affecting the receptors for the epidermal growth factor. The inhibition of growth of the Mia PaCa-2 cells in culture was also evaluated to determine the mechanism of action of somatostatin analogues and their relative effectiveness in inhibiting cancer growth. Of the analogues tested D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) caused the greatest stimulation of tyrosine phosphatase activity. Analogue D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121) had less effect but was more potent than somatostatin-14. Analogue D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol) (SMS 201-995) produced no significant dephosphorylation. The analogues displayed the same order of activity in assays on growth inhibition of Mia PaCa-2 cells in cultures. Analogue (SMS-201-995) caused virtually no tyrosine phosphatase stimulation or growth inhibition in this cancer cell line, although it possesses a much higher antisecretory activity than somatostatin-14 in normal tissues. These observations indicate that somatostatin and some of its analogues can act as growth inhibitors in cancer cells through the activation of tyrosine phosphatase. These data reinforce the view that somatostatin analogue RC-160 and related compounds could be used for treatment of pancreatic cancer.
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PMID:Somatostatin analogues inhibit growth of pancreatic cancer by stimulating tyrosine phosphatase. 256 78

Inhibition by seven synthetic 4-hydroxycinnamamide derivatives, ST 271, ST 280, ST 458, ST 494, ST 633, ST 638, and ST 642, of tyrosine-specific protein kinases (tyrosine kinase) of oncogene or proto-oncogene products (p130gag-v-fps, p70gag-actin-v-fgr, pp60v-src, pp60c-src) and epidermal growth factor (EGF) receptor kinase were investigated. ST 638 (alpha-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamamide) strongly inhibited more of the tyrosine kinases than any of the other compounds. The susceptibilities of these tyrosine kinases to ST 638 increased in the following order: EGF receptor greater than p70gag-actin-v-fgr greater than pp60c-src greater than p130gag-v-fps, pp60v-src, with 50% inhibitory concentration values of 1.1, 4.2, 18, 70, and 87 microM, respectively. The phosphorylation of the tyrosine residues in particulate fractions from RR1022 cells expressing pp60v-src was inhibited by ST 638 in a dose-dependent way, while it had a negligible effect on the phosphorylations of threonine and serine residues. Kinetic analysis showed that ST 638 competitively inhibited the phosphorylation of an exogenous substrate by the EGF receptor kinase with a Ki of 2.1 microM. ST 638 noncompetitively inhibited autophosphorylation by EGF receptor kinase. These results indicate that ST 638 is a potent and specific inhibitor of tyrosine kinases in vitro, and that its inhibitory activity is caused by competing with the substrate protein for the tyrosine kinase binding site.
Cancer Res 1989 May 01
PMID:Specific inhibitors of tyrosine-specific protein kinases: properties of 4-hydroxycinnamamide derivatives in vitro. 270 25

A high molecular weight, mucous glycoprotein (MG) from the pleural fluid of lung adenocarcinoma was purified by the DEAE-cellulose, gel-filtration and wheat germ agglutinin affinity chromatography. Protein portion of the molecule was composed of amino acids rich in serine, threonine and proline, but methionine and tyrosine concentrations were relatively low. About 65% of the weight, was composed of galactose, galactosamine, glucosamine, fucose and sialic acid. The gel-filtration pattern on Sepharose 4B revealed Mr greater than 10(6) Da. The SDS-PAGE pattern revealed a main band at the position of the Mr about 350 kDa under the reducing condition. Rabbit antibody against this molecule recognized mainly the peptide portion, and the radioimmunoassay (RIA) using the double antibody method was developed by this antibody. Serum MG level was low in healthy subjects and in benign diseases (0.8 +/- 0.7 U/ml; mean +/- SD and 1.1 +/- 2.3 U/ml, respectively). Thus, 3 U/ml was used as the cut-off value. The mean of serum MG levels and positive rates in malignant diseases were significantly high; 4.4 U/ml and 32.3% in lung cancer, 20.1 U/ml and 77.5% in pancreas cancer 11.6 U/ml and 64.3% in gastric cancer, 12.9 U/ml and 57.1% in hepatoma, 12.3 U/ml and 77.8 in colon cancer. Other malignancies such as ovarial and uterus cancer showed also high levels. Elevated values in these malignancies were observed frequently in patients with metastasis. On the other hand, the false positive cases were found in 10% of benign diseases. Determination of MG seems to be useful for the detection of several kinds of malignancies, but it is not adequately sensitive as a screening method for early cancer detection.
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PMID:Clinical significance of mucin-like high molecular weight glycoprotein originated from lung cancer as tumor marker. 274 68

Tumor cell metastasis involves a complex series of interdependent events, including repeated invasion of basement membranes. Studies from several laboratories have implicated tumor cell adhesion and migration in response to laminin as a major contributing factor in tumor cell invasion. The current studies address the direct role of type IV collagen in promoting tumor cell adhesion, spreading, and migration. The observations of type IV collagen-mediated cellular behavior are contrasted with cellular behavior on type I collagen. The highly metastatic K1735 M4 melanoma cell line adhered, spread, and migrated in response to type IV collagen in a concentration-dependent manner. Functional assays using well-defined proteolytic fragments of type IV collagen demonstrated that melanoma cells interact with multiple domains of this protein. Highly metastatic melanoma cells adhered, spread, and exhibited motile behavior in response to 0.2 to 200 nM concentrations of a purified pepsin-generated, triple helix-rich domain of type IV collagen. In contrast, cells adhered and spread but were essentially nonmotile in response to a purified major noncollagenous domain of the protein. In addition, de novo protein synthesis was required for cell adhesion to the major noncollagenous domain, whereas adhesion to the helical domain was less dependent upon de novo protein synthesis. Arg-Gly-Asp (RGD)-related peptides were used to study the adhesion and spreading of melanoma cells on type IV collagen. The results demonstrated that a serine containing RGD-related peptide (GRGDSP) has virtually no effect on melanoma cell adhesion on type IV collagen-coated substrata, whereas this peptide inhibited melanoma cell adhesion to fibronectin-coated substrata in a concentration-dependent manner. In contrast, when threonine was substituted for serine (GRGDTP), cell adhesion to type IV collagen was significantly (45%) inhibited. The threonine-containing peptide virtually eliminated cell adhesion on substrata coated with type I collagen. These data demonstrate that adhesion, spreading, and migration of melanoma cells on type IV collagen have a complex molecular basis which is partially dependent on RGD-related sequences.
Cancer Res 1989 Sep 01
PMID:Type IV collagen-mediated melanoma cell adhesion and migration: involvement of multiple, distinct domains of the collagen molecule. 275 12

Taxol is an inhibitor of cell replication that promotes the assembly of microtubules in vitro and in cells. In the murine macrophage-like cell line J774.2, a taxol-resistant subline (J7/TAX-50) has been developed in vitro by growing the cells in increasing drug concentrations. These cells, which are approximately 800-fold resistant to taxol, display some cross-resistance to colchicine, vinblastine, puromycin, doxorubicin, and actinomycin D but remain sensitive to bleomycin. Binding of radiolabeled drug to the resistant cells is reduced by approximately 90%. Resistant cells grown in the absence of drug for 10 days (J7/TAX-0D10), 1 month (J7/TAX-0D30), and 8 months (J7/TAX-0D240) regain a major portion (27, 92, and 99%, respectively) of their sensitivity to the drug. However, binding of the drug to the J7/TAX-0D30 and J7/TAX-0D240 cells is increased to only 20 and 70%, respectively, of that measured with sensitive cells. Analysis of plasma membranes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by silver staining reveals the presence of a prominent protein with an approximate molecular weight of 135,000 in the resistant line that is essentially absent from the parental line and from both of the J7/TAX-0D30 and J7/TAX-0D240 lines. Although this protein can be seen in J7/TAX-0D10, its quantity is diminished. The Mr 135,000 protein is also observed in the resistant cells when they are labeled with [3H]leucine, [35S]methionine, [3H]glucosamine, or [32P]orthophosphate. Plasma membranes from colchicine- or vinblastine-resistant J774.2 cells also contain prominent phosphoglycoproteins, with approximate molecular weights of 145,000 and 150,000, respectively. Partial purification of the Mr 135,000 glycoprotein by agarose-bound ricinus communis agglutinin I-agarose affinity chromatography indicates that it accounts for approximately 4 to 5% of total membrane protein. A Mr 100,000 phosphoglycoprotein, present in the membranes of J774.2 cells is essentially absent in J7/TAX-50 cells after labeling with [3H]glucosamine or [32P]orthophosphate. Phosphoamino acid analysis of the Mr 135,000 and 100,000 phosphoglycoproteins reveals that the phosphorylation sites are serine and threonine residues. There appears to be a good correlation between the presence of the Mr 135,000 phosphoglycoprotein in plasma membranes and resistance to taxol.
Cancer Res 1985 Aug
PMID:A phosphoglycoprotein associated with taxol resistance in J774.2 cells. 286 92

Mucin glycoproteins are major secretory products of the colon and contain O-linked oligosaccharides synthesized on a polypeptide backbone. The initial step in the synthesis of O-linked oligosaccharides is the addition of N-acetylgalactosamine to serine or threonine residues forming the Tn antigen. This substance can then receive additional carbohydrate residues such as sialic acid to form sialosyl-Tn antigen, or galactose to form T antigen. In the colon, the T antigen is an oncodevelopmental cancer-associated antigen but little is known about Tn and sialosyl-Tn expression. The present comparative immunohistochemical study was performed to analyze the expression of these antigens in fetal, normal adult, and malignant colorectal tissues with an aim toward elucidating whether Tn and sialosyl-Tn are also oncodevelopmental colon cancer-associated antigens and to gain insight into the earliest steps of mucin glycosylation in colonocytes. We used three reagents to detect Tn antigen (two monoclonal antibodies ETn1.01 and CU-1, and one lectin Vicia villosa), two reagents to detect sialosyl-Tn (monoclonal antibodies TKH2 and B72.3) and one to detect T antigen (monoclonal antibody AH9-16). Except for occasional reactivity with VVA and CU-1, cells of normal colonic mucosa did not express Tn, sialosyl-Tn, or T antigens. However, in the transitional mucosa immediately adjacent to cancer, all three antigens were expressed (ranging from 35 to 67% of cases depending upon the reagent). In colon cancers, the percentage of cases expressing each antigen were as follows: Tn 72-81%, sialosyl-Tn 93-96%, and T 71%. Unlike T antigen, which was preferentially expressed by moderately well- and well-differentiated adenocarcinomas, both Tn and sialosyl-Tn antigens were expressed by most histological subsets of colon cancers, including poorly differentiated adenocarcinomas and mucinous (colloid and signet ring cell type) carcinomas. The majority of cancers expressed both Tn and sialosyl-Tn, usually in association with T antigen. Only one cancer lacked all three antigens. Fetal colonic mucosal cells expressed all three antigens, particularly in goblet cell mucin. These results indicate that like T antigen, Tn and sialosyl-Tn are oncodevelopmental cancer-associated antigens in the colon. Moreover, Tn and sialosyl-Tn antigens appear to be useful markers of poorly differentiated adenocarcinomas and mucinous carcinomas: two histological subsets that often fail to express other cancer-associated antigens and that are often associated with a poor clinical outcome.(ABSTRACT TRUNCATED AT 400 WORDS)
Cancer Res 1989 Jan 01
PMID:Expression of Tn, sialosyl-Tn, and T antigens in human colon cancer. 290 46

Complementary DNAs corresponding to the human receptor for interleukin 2 (IL-2) have been molecularly cloned, sequenced, and expressed in COS-1 cells. The human genome appears to contain a single structural gene for this receptor; however, when transcribed at least two messenger RNAs (mRNAs) are produced which vary in length due to the use of different polyadenylation signals. Sequence analysis of the cloned complementary DNAs indicates an alternate pathway of mRNA processing for this receptor. Splicing of a 216 base pairs segment contained within the protein coding region results in an mRNA unable to code for the IL-2 receptor. In contact complementary DNAs corresponding to unspliced mRNA encode membrane receptors which bind both IL-2 and anti-Tac (monoclonal anti-IL-2 receptor antibody). Analysis of the deduced amino acid sequence reveals that the receptor is composed of 272 amino acids including a signal peptide 21 amino acids in length. Hydrophobicity analysis suggests a single 19 amino acid transmembrane domain. A short intracytoplasmic domain composed of 13 amino acids is present at the carboxy terminus and contains three potential phosphate acceptor sites (serine and threonine but not tyrosine) and typical positively charged amino acids presumably involved in cytoplasmic anchoring. Two sites for N-linked glycosylation sites and numerous extracytoplasmic O-linked glycosylation sites are present.
Cancer Res 1985 Sep
PMID:Isolation and expression of complementary DNAs encoding the human interleukin 2 receptor. 299 Jun 88

In contrast to healthy and noncarcinoma-diseased tissues, greater than 80% of all carcinomas (CAs) tested express immunoreactive O-(2-acetamido-2-deoxy-alpha-D-galacto-pyranosyl)-(1----3)-serine/threon ine [alpha-D-GalpNAc-(1----3)-Ser/Thr] in their glycoproteins. CA cells shed, into the tumor's environment, Tn, which is involved in cancer pathogenesis as adhesion molecule and as autoimmunogen. An increase in density of Tn on primary CA frequently parallels augmented CA aggressiveness. Tn-Active glycoproteins of culture-grown human breast CA DU 4475 cells were isolated from cytoplasm and from spent growth medium, and erythrocyte (RBC) Tn antigen was prepared by (1----3)-beta-D-galactosidase treatment of isolated human O RBC MN glycoprotein-derived Thomsen-Friedenreich (T) antigen. Immunochemical, serological, physical, and chemical analyses showed close resemblance of CA- and RBC-derived Tn antigens. The preponderant carbohydrate in both Tn glycoproteins is the alpha-D-GalpNAc residue, and the antigens have a qualitatively and quantitatively similar amino acid composition. Highly specific rodent monoclonal (Mo) anti-Tn antibodies (Abs) were elicited with Tn RBC and normal O RBC-derived Tn antigen, and compared with CA-anti-Tn MoAbs unwittingly evoked by others. A sensitive enzyme immunoassay (EIA) with Tn antigen as solid phase was developed. In this system, highly purified, "naturally occurring" anti-Tn antibodies, which all humans possess, were more sensitive in quantitating breast CA Tn structures than the anti-Tn MoAbs induced by Tn RBCs, and by RBC- and CA-derived Tn-active antigens. The sensitivity of anti-Tn MoAbs was higher in detecting RBC-Tn.
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PMID:Blood group Tn-active macromolecules from human carcinomas and erythrocytes: characterization of and specific reactivity with mono- and poly-clonal anti-Tn antibodies induced by various immunogens. 305 14


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