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Sybille Mazurek

Publications and source records attributed to Sybille Mazurek.

7 recordsLinked to original sources
PubMed2007

Interference with energy metabolism by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside induces HPV suppression in cervical carcinoma cells and apoptosis in the absence of LKB1.

Carcinogenesis is a dynamic and stepwise process, which is accompanied by a variety of somatic and epigenetic alterations in response to a changing microenvironment. Hypoxic conditions will select for cells that have adjusted their metabolic profile and can maintain proliferation by successfully competing for scarce nutritional and oxygen resources. In the present study we have investigated the effects of energy depletion in the context of HPV (human papillomavirus)-induced pathogenesis. We show that cervical carcinoma cell lines are susceptible to undergoing either growth arrest or cell death under conditions of metabolic stress induced by AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside), a known activator of the AMPK (AMP-activated protein kinase). Our results reveal that AICAR treatment leads to a reduced binding affinity of the transcription factor AP-1 (activator protein-1) and in turn to a selective suppression of HPV transcription. Moreover, the outcome of AICAR on proliferation and survival was dependent on p53 activation and the presence of LKB1, the major upstream kinase of AMPK. Using non-malignant LKB1-expressing somatic cell hybrids, which lose expression after tumorigenic segregation, as well as small interfering RNA LKB1 knockdown approaches, we could further demonstrate that expression of LKB1 protects cells from cytotoxicity induced by agents which modulate the ATP/AMP ratio. Since simulation of low energy status can selectively eradicate LKB1-negative cervical carcinoma cells, AICAR may represent a novel drug in the treatment of cervical cancer.

AMP-Activated Protein Kinase Kinases↗
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

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↗
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↗