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001-es BibID:BIBFORM050093
Első szerző:Petrás Miklós (orvos)
Cím:Molecular interactions of ErbB1 (EGFR) and integrin-β1 in astrocytoma frozen sections predict clinical outcome and correlate with Akt-mediated in vitro radioresistance / Miklós Petrás, Tamás Lajtos, Elza Friedländer, Álmos Klekner, Éva Pintye, Burt G. Feuerstein, János Szöllősi, György Vereb
Dátum:2013
ISSN:1522-8517
Megjegyzések:INTRODUCTION: Treatment of astrocytoma is frequently hampered by radioresistance of the tumor. In addition to overexpression of ErbB1/EGFR, functional crosstalk between receptor tyrosine kinases and cell adhesion molecules may also contribute to therapy resistance. METHODS: Acceptor photobleaching FRET was implemented on frozen sections of clinical astrocytoma to check the role of ErbB1-integrin-beta1 interaction. U251 glioma subclones were obtained by introducing extra CHR7 material or the ErbB1 gene to test the relevance and mechanism of this interaction in vitro. RESULTS: Grade IV tumors showed higher ErbB1 and integrin-beta1 expression and greater ErbB1-integrin-beta1 heteroassociation than did grade II tumors. Of these, the extent of molecular association was a single determinant of tumor grade and prognosis in stepwise logistic regression. In vitro, integrin-beta1 was upregulated, and radiosensitivity was diminished by ectopic ErbB1 expression. Great excess of ErbB1 provided colony forming advantage over medium excess but did not yield better radiation resistance or faster proliferation and decreased to medium level over time, whereas integrin-beta1 levels remained elevated and defined the extent of radioresistance. Increased expression of ErbB1 and integrin-beta1 was paralleled by decreasing ErbB1 homoassociation and increasing ErbB1-integrin-beta1 heteroassociation. Microscopic two-sided FRET revealed that pixels with higher ErbB1-integrin-beta1 heteroassociation exhibited lowed ErbB1 homoassociation, indicating competition for association partners among these molecules. Boosted Akt phosphorylation response to EGF accompanied this shift toward heteroassociation, and the consequentially increased radioresistance could be reverted by inhibiting PI3K. CONCLUSION: The clinically relevant ErbB1-integrin-beta1 heteroassociation may be used as a target of both predictive diagnostics and molecular therapy
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Biophysics
Cell Adhesion
Cell Adhesion Molecules
cell biology
EGFR
ErbB1
EXPRESSION FRET
Glioma
Hungary
In Vitro
methods
molecular interaction
Phosphorylation
Photobleaching
Receptor
tyrosine kinase
Research
therapy
TUMORS
Tyrosine
Molekulatudomány
Doktori iskola
Megjelenés:Neuro-Oncology. - 15 : 8 (2013), p. 1027-1040. -
További szerzők:Lajtos Tamás Friedländer Elza (1980-) (biofizikus) Klekner Álmos (1970-) (idegsebész) Pintye Éva (1955-) (fizikus) Feuerstein, Burt G. Szöllősi János (1953-) (biofizikus) Vereb György (1965-) (biofizikus, orvos)
Pályázati támogatás:K75752
OTKA
NK101337
OTKA
F-049050
OTKA
ETT 523/2003
Egyéb
ETT 362-01/2009
Egyéb
TÁMOP-4.2.1/B-09/1/KONV-2010-0007
TÁMOP
TÁMOP-4.2.2/B-10/1-2010-0024
TÁMOP
TÁMOP-4.2.2/A-11/1/KONV-2012-0025
TÁMOP
Internet cím:Szerző által megadott URL
DOI
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2.

001-es BibID:BIBFORM042489
Első szerző:Petrás Miklós (orvos)
Cím:Significance of Epidermal Growth Factor Receptor in the Radiation Resistance of Glioblastoma Tumors / Miklós Petrás, Tamás Lajtos, Éva Pintye, Burt G. Feuerstein, János Szöllősi, György Vereb
Dátum:2008
Megjegyzések:In the United States, a dramatically increased incidence and mortality of brain tumors have been observed over the past decades. Of the ~44 thousand new cases of primary malignant and benign brain tumors diagnosed per year, highgrade astrocytomas or multiform glioblastomas show particularly bad prognosis in spite of therapeutic developments. Current management of multiform glioblastoma includes the most extensive surgical resection possible, followed by adjuvant radio- and chemotherapy. However, treatment is frequently hampered by decreased radiosensitivity of the tumor. Recent studies revealed that subpopulations of glioblastoma cells show amplified checkpoint activation of the cell cycle upon ionizing radiation, which induces overactivation of DNA repair processes and leads to maintained proliferation rate as well as clinically observed radioresistance and recurrence of the tumor over time. In addition, overexpression of some transmembrane receptors has also been implicated in radioresistance. However, the role of the overexpressed proteins can only be interpreted reliably if their multi-faceted molecular interactions are properly characterized. Thus, based on recent evidence for the functional crosstalk between certain cell adhesion molecules andreceptor tyrosine kinases, we have examined the molecular interactions of the receptor tyrosine kinase EGFR and the cell adhesion molecule 1-integrin using flow cytometric and microscopic fluorescence resosnance energy transfer (FRET)measurements on two cellular model systems showing similar expression patterns to low and high grade astrocytomas. On the one hand, U251 glioblastoma clones established by introducing varying amounts of extra chromosome 7 into the cells, and on the other hand stable, high and low EGFR expressing transfenctant U251 NCI sublines were investigated. The results revealed that increased EGFR and 1-integrin expression levels correlate with stronger EGFR ? 1-integrin heteroassociation, while concurrently the EGFR homoassociation is decreased, suggesting that 1-integrins may dynamically modulate the homoassociation state of EGFR receptors. This functional relationship may play an important role in decreasing radiosensitivity and tumor progression, especially since the EGFR ? 1-integrin molecular interaction appears to promote radioresistance via the Akt pathway.
ISBN:978-0-7354-0611-7
Tárgyszavak:Orvostudományok Elméleti orvostudományok könyvfejezet
Megjelenés:Radiation Damage In Biomolecular Systems : Proceedings of the 5th International Conference (RADAM 2008) / ed. by Károly Tőkési, Béla Sulik. - p. 204-217. -
További szerzők:Lajtos Tamás Pintye Éva (1955-) (fizikus) Feuerstein, Burt G. Szöllősi János (1953-) (biofizikus) Vereb György (1965-) (biofizikus, orvos)
Internet cím:DOI
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3.

001-es BibID:BIBFORM050058
Első szerző:Schwarzenberg, Karin von
Cím:V-ATPase inhibition overcomes trastuzumab resistance in breast cancer / Karin von Schwarzenberg, Tamás Lajtos, László Simon, Rolf Müller, György Vereb, Angelika M. Vollmar
Dátum:2014
Megjegyzések:The HER2 oncogene targeting drug trastuzumab shows remarkable efficacy in patients overexpressing HER2. However acquired or primary resistance develops in most of the treated patients why alternative treatment strategies are strongly needed. As endosomal sorting and recycling are crucial steps for HER2 activity and the vacuolar H(+)-ATPase (V-ATPase) is an important regulator of endocytotic trafficking, we proposed that targeting V-ATPase opens a new therapeutic strategy against trastuzumab-resistant tumor cells in vitro and in vivo. V-ATPase inhibition with archazolid, a novel inhibitor of myxobacterial origin, results in growth inhibition, apoptosis and impaired HER2 pro-survival signaling of the trastuzumab-resistant cell line JIMT-1. This is accompanied by a decreased expression on the plasma membrane and accumulation of HER2 in the cytosol, where it colocalizes with endosomes, lysosomes and autophagosomes. Importantly, microscopic analysis of JIMT-1 xenograft tumor tissue of archazolid treated mice confirms the defect in HER2-recycling which leads to reduced tumor growth. These results suggest that V-ATPase inhibition by archazolid induces apoptosis and inhibits growth of trastuzumab-resistant tumor cells by retaining HER2 in dysfunctional vesicles of the recycling pathway and consequently abrogates HER2-signaling in vitro as well as in vivo. V-ATPase inhibition is thus suggested as a promising strategy for treatment of trastuzumab-resistant tumors
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
analysis
Apoptosis
article
Biophysics
cell biology
Cell Line
Cells
Cytosol
Endosomes
EXPRESSION
GROWTH
Hungary
In Vitro
Mice
Research
Trastuzumab resistance
TUMORS
Megjelenés:Molecular Oncology. - 8 : 1 (2014), p. 9-19. -
További szerzők:Lajtos Tamás Simon László (biofizikus) Müller, Rolf Vereb György (1965-) (biofizikus, orvos) Vollmar, Angelika M.
Internet cím:DOI
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