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Erich Eigenbrodt

Publications and source records attributed to Erich Eigenbrodt.

11 recordsLinked to original sources
PubMed2005

Pyruvate kinase type M2 and its role in tumor growth and spreading.

Proliferating cells and tumor cells in particular express the pyruvate kinase isoenzyme type M2 (M2-PK). Within the tumor metabolome M2-PK regulates the proportions of glucose carbons that are channelled to synthetic processes (inactive dimeric form) or used for glycolytic energy production (highly active tetrameric form, a component of the glycolytic enzyme complex). In tumor cells, the dimeric form of M2-PK (Tumor M2-PK) is always predominant. The dimerization is caused by direct interaction of M2-PK with certain oncoproteins. The switch between the tetrameric and dimeric form of M2-PK allows tumor cells to survive in environments with varying oxygen und nutrient supply.

Animals↗
PubMed2004

Phosphoglycerate mutase-derived polypeptide inhibits glycolytic flux and induces cell growth arrest in tumor cell lines.

The putative tumor metastasis suppressor protein Nm23-H1 is a nucleoside diphosphate kinase that exhibits a novel protein kinase activity when bound to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In this study we show that the glycolytic enzyme phosphoglycerate mutase B (PGM) becomes phosphorylated in the presence of the Nm23-H1.GAPDH complex in vitro. Mutation of His-10 in PGM abolishes the Nm23-H1.GAPDH complex-induced phosphorylation. Nm23-H1, GAPDH, and PGM are known to co-localize as shown by free flow isoelectric focusing. In association with Nm23-H1 and GAPDH, PGM could be activated by dCTP, which is a substrate of Nm23-H1, in addition to the well known PGM activator 2,3-bisphosphoglycerate. A synthetic cell-penetrating peptide (PGMtide) encompassing the phosphorylated histidine and several residues from PGM (LIRHGE) promoted growth arrest of several tumor cell lines, whereas proliferation of tested non-tumor cells was not influenced. Analysis of metabolic activity of one of the tumor cell lines, MCF-7, indicated that PGMtide inhibited glycolytic flux, consistent with in vivo inhibition of PGM. The specificity of the observed effect was further determined experimentally by testing the effect of PGMtide on cells growing in the presence of pyruvate, which helps to compensate PGM inhibition in the glycolytic pathway. Thus, growth of MCF-7 cells was not arrested by PGMtide in the presence of pyruvate. The data presented here provide evidence that inhibition of PGM activity can be achieved by exogenous addition of a polypeptide, resulting in inhibition of glycolysis and cell growth arrest in cell culture.

Cell Line, Tumor↗
PubMed2003

Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence.

Cellular senescence is considered a major tumour-suppressor mechanism in mammals, and many oncogenic insults, such as the activation of the ras proto-oncogene, trigger initiation of the senescence programme. Although it was shown that activation of the senescence programme involves the up-regulation of cell-cycle regulators such as the inhibitors of cyclin-dependent kinases p16INK4A and p21CIP-1, the mechanisms underlying the senescence response remain to be resolved. In the case of stress-induced premature senescence, reactive oxygen species are considered important intermediates contributing to the phenotype. Moreover, distinct alterations of the cellular carbohydrate metabolism are known to contribute to oncogenic transformation, as is best documented for the phenomenon of aerobic glycolysis. These findings suggest that metabolic alterations are involved in tumourigenesis and tumour suppression; however, little is known about the metabolic pathways that contribute to these processes. Using the human fibroblast model of in vitro senescence, we analysed age-dependent changes in the cellular carbohydrate metabolism. Here we show that senescent fibroblasts enter into a metabolic imbalance, associated with a strong reduction in the levels of ribonucleotide triphosphates, including ATP, which are required for nucleotide biosynthesis and hence proliferation. ATP depletion in senescent fibroblasts is due to dysregulation of glycolytic enzymes, and finally leads to a drastic increase in cellular AMP, which is shown here to induce premature senescence. These results suggest that metabolic regulation plays an important role during cellular senescence and hence tumour suppression.

Adenosine Monophosphate↗
PubMed2003

Tumor M2-pyruvate kinase in the follow-up of inoperable lung cancer patients: a pilot study.

Tumor markers were used for disease monitoring in lung cancer patients. The goal of this pilot study was to determine the diagnostic efficiency of a new tumor metabolic marker, Tumor M2-pyruvate kinase (Tumor M2-PK) for the detection of tumor growth in inoperable lung cancer patients.Fifty-seven consecutive and primary inoperable lung cancer patients were included in this prospective study. Changes in plasma levels of Tumor M2-PK were compared to the clinical course of the disease. Clinical monitoring was evaluated according to the standard criteria of the WHO. Of the 57 patients, 19 were in remission, 18 showed signs of stable disease and there were 20 tumor progressions under therapy. In the further follow-up after treatment, tumor relapse occurred in 30 patients. Tumor M2-PK was measured in plasma before and after treatment as well as at time of relapse. During tumor remission Tumor M2-PK levels decreased significantly under treatment (P=0.0004). As might be expected, pre- and post-treatment marker concentrations did not differ significantly in patients with stable disease. In progressive lung cancer patients a significant increase in Tumor M2-PK was detectable (P=0.0094). Overall, a decrease of Tumor M2-PK was seen in 17 (89%) of all responders, while an increase could be detected in 16 (80%) of the patients experiencing tumor progression. After treatment tumor relapse occurred in 30 patients. Tumor M2-PK increased significantly (P=0.0201) at time of relapse in 17 patients with non-small cell lung cancers and exceeded the cut-off in 11 of the 17 (65%). In conclusion, Tumor M2-PK proved useful as a diagnostic aid for therapy control in lung cancer patients. This marker can also be used to detect tumor relapse after treatment. Tumor M2-PK could be well suited to complete the present diagnostic panel for monitoring of inoperable lung cancer patients.

Age Factors↗
PubMed2003

Interaction between HERC1 and M2-type pyruvate kinase.

HERC proteins are characterized by having one or more RCC1-like domains as well as a C-terminal HECT domain in their amino acid sequences. This has led researchers to suggest that they may act as both guanine nucleotide exchange factors and E3 ubiquitin ligases. Here we describe a physical interaction between the HECT domain of HERC1, a giant protein involved in intracellular membrane traffic, and the M2 isoform of glycolytic enzyme pyruvate kinase (M2-PK). Partial colocalization of endogenous proteins was observed by immunofluorescence studies. This interaction neither induced M2-PK ubiquitination nor affected its enzymatic activity. The putative significance of the association is discussed.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Fuzzy logic-based tumor-marker profiles improved sensitivity in the diagnosis of lung cancer.

BACKGROUND: The aim of this study was to improve the diagnostic efficiency of tumor markers in the diagnosis of lung cancer, by the mathematical evaluation of a tumor marker profile employing fuzzy logic modelling. METHODS: A panel of four tumor markers, i.e., carcinoembryonic antigen (CEA), cytokeratin 19 antibody (CYFRA 21-1), neuron-specific enolase (NSE), squamous cell carcinoma-related antigen (SCC) and, additionally, C-reactive protein (CRP), was measured in 175 newly diagnosed lung cancer patients with different histological types and stages. Results were compared with those in 120 control subjects, including 27 with chronic obstructive pulmonary diseases (COPD), 65 with pneumoconiosis, and 11 persons with acute inflammatory lung diseases. A classificator was developed using a fuzzy-logic rule-based system. RESULTS: Application of the fuzzy-logic rule-based system to the tumor marker values of CYFRA 21-1, NSE, and CRP yielded an increase in sensitivity of approximately 20%, i.e., 92%, compared with that of the best single marker, CYFRA 21-1(sensitivity, 72%). The corresponding specificity was 95%. The fuzzy classificator significantly improved the sensitivity of the tumor marker panel in stages I and IIIa for non-small-cell lung cancer, as well as in "limited disease" status for small-cell lung cancer. Also, the diagnosis of other stages of lung cancer was enhanced. CONCLUSION: Fuzzy-logic analysis was proven to be more powerful than the measurement of single markers alone or combinations using multiple logistic regression analysis of all markers. Therefore, fuzzy logic offers a promising diagnostic tool to improve tumor marker efficiency.

Aged↗
PubMedDate not supplied

Tumor M2-pyruvate kinase in lung cancer patients: immunohistochemical detection and disease monitoring.

BACKGROUND: Lung cancer is one of the main causes for cancer death. A reliable diagnosis and follow-up of patients is important support for a successful therapy. The diagnostic efficiency of a new marker Tumor M2-pyruvate kinase (Tumor M2-PK) is evaluated. MATERIALS AND METHODS: In this report immunohistochemical detection of pyruvate kinase M2 in tissue sections of lung cancer specimens is presented. Furthermore Tumor M2-PK was quantified in EDTA plasma of lung cancer patients in order to monitor the disease, especially under chemotherapy. RESULTS: Immunohistochemical detection of pyruvate kinase M2 in tissue sections of lung cancer specimens showed selective staining of tumor cells, independent of the histological classification of the tumor. In EDTA plasma of lung cancer patients, the marker concentrations correlated well with the tumor load during follow-up, showing significantly increasing concentrations with progressive tumor stages and decreased concentrations during tumor remission. Again, this effect was independent of the histological tumor type. CONCLUSION: The present data indicate that Tumor M2-PK in EDTA-plasma could be a valuable tumor marker for monitoring lung cancer.

Aged↗
PubMedDate not supplied

Fuzzy logic-based tumor marker profiles including a new marker tumor M2-PK improved sensitivity to the detection of progression in lung cancer patients.

In lung cancer patients tumor markers are used for disease monitoring. The goal of this study was to improve diagnostic efficiency in the detection of tumor progression in lung cancer patients by using fuzzy logic modeling in combination with a tumor marker panel (Tumor M2-PK, CYFRA 21-1, CEA, NSE and SCC). Thirty-three small cell lung cancers (SCLC) and 69 consecutive inoperable patients (40 squamous and 29 adenocarcinomas) were included in a prospective study. The changes of blood levels of tumor markers as well as their analysis by fuzzy logic modelling were compared to the clinical evaluation of response vs. non-response to therapy. Clinical monitoring was evaluated according to the standard criteria of the WHO. Tumor M2-PK was measured in plasma with an ELISA (ScheBo Biotech, Germany) and all other markers in sera (Roche, Germany). At a 90% specificity, the respective best single marker found the following fraction of all patients who had tumor progression clinically detected: in SCLC with NSE 52%, in adenocarcinoma with CYFRA 21-1 89% and in squamous carcinoma with SCC 65%. A fuzzy logic rule-based system employing a tumor marker panel increased the sensitivity in small cell carcinomas to 73% with the marker combination NSE/CEA and to 63% with the marker combination NSE/Tumor M2-PK, respectively. In squamous carcinomas an improvement of sensitivity is also observed using the marker combination of SCC/Tumor M2-PK (Sensitivity: 81%) or SCC/CEA (Sensitivity: 71%). By using the fuzzy logic method and the marker combination CYFRA 21-1/CEA as well as CYFRA 21-1/Tumor M2-PK, the detection of lung cancer progression was possible in all adenocarcinomas. With the fuzzy logic method and a tumor marker panel (including the new marker Tumor M2-PK), a useful diagnostic tool for the detection of progression in lung cancer patients is available.

Adenocarcinoma↗
PubMedDate not supplied

The tumor metabolome.

The tumor metabolome is characterized by high glycolytic and glutaminolytic capacities, high phosphometabolite levels and a high channelling of glucose carbons to synthetic processes. This allows tumor cells to proliferate under strong variations in oxygen and glucose supply (http://www.metabolic-database.com). One key regulator of the tumor metabolome is the glycolytic isoenzyme pyruvate kinase type M2 (M2-PK) that is generally over-expressed in all tumor cells. M2-PK can occur in a highly active tetrameric form and in a nearly inactive dimeric form. In tumor cells the dimeric form of M2-PK always predominates and has therefore been termed tumor M2-PK. The dimerization of M2-PK is caused by direct interaction of M2-PK with certain oncoproteins. When M2-PK is in its dimeric state energy is produced by glutaminolysis. The metabolic Achilles' heel of the tumor metabolome is its sensitivity to a reduction of NAD levels caused by activation of poly(ADP-ribose) polymerase after DNA damage.

Genome, Human↗
PubMedDate not supplied

Value of tumor M2-PK in thyroid carcinoma: a pilot study.

BACKGROUND: Tumor M2-PK (Tu M2-PK) as the inactive dimeric form of pyruvate kinase M2 has been proven to be elevated in breast, lung, renal and gastrointestinal malignancies. We compared this marker in 26 patients with metastatic thyroid carcinoma using the established tumor marker thyroglobulin (Tg). MATERIALS AND METHODS: Plasma Tu M2-PK was measured using an ELISA assay (Schebo Biotech, Giessen, Germany) and Tg was measured in serum using an electrochemiluminescence Immunoassay (Tg Elecsys Systems, Roche, Germany), as a part of the routine follow-up of the patients. RESULTS: At a cut-off of 15 U/ml, Tu M2-PK was elevated in 50% of the patients; at a cut-off of 20 U/ml (grey zone 15-20 U/ml), Tu M2-PK was elevated in 27% of the patients. The correlation coefficient between serum Tg level and Tu M2-PK was -0.093. CONCLUSION: Tu M2-PK is less valuable for the detection of malignant thyroid disease than Tg.

Biomarkers, Tumor↗