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Schilling, D. ; Düwel, M.* ; Molls, M.* ; Multhoff, G.

Radiosensitization of wildtype p53 cancer cells by the MDM2-inhibitor PXN727 is associated with altered Heat shock protein 70 (Hsp70) levels.

Cell Stress Chaperones 18, 183-191 (2013)
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The oncoprotein MDM2 (murine double minute 2) is often overexpressed in human tumors and thereby attenuates the function of the tumor suppressor p53. In this study, we investigated the effects of the novel MDM2-inhibitor PXN727 on p53 activation, cell proliferation, cell cycle distribution and radiosensitivity. Since the localization of heat shock protein 70 (Hsp70) exerts different effects on radioresistance of tumor cells, we investigated the impact of PXN727 on intracellular, membrane, and secreted Hsp70 levels. We could show that PXN727 exerts its effects on wildtype p53 (HCT116 p53(+/+), A549) but not p53 depleted (HCT116 p53(-/-)) or mutated (FaDu) tumor cells. PXN727 activates p53, induces the expression of p21, reduces the proportion of cells in the radioresistant S-phase and induces senescence. Radiosensitivity was significantly increased by PXN727 in HCT116 p53(+/+) tumor cells. Furthermore, PXN727 causes a downregulation of Hsp70 membrane expression and an upregulated secretion of Hsp70 in wildtype p53 tumor cells. Our data suggest that re-activation of p53 by MDM2-inhibition modulates Hsp70 membrane expression and secretion which might contribute to the radiosensitizing effect of the MDM2-inhibitor PXN727.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Hsp70; PXN727; MDM2; p53; Radiosensitization; Membrane-bound Heat-shock-protein-70 ; Natural-killer-cells ; Mdm2-p53 Interaction ; Cytolytic Activity ; Tumor-cells ; Senescence ; Nutlin-3 ; Inhibitor ; Sensitivity ; Radiation
Sprache englisch
Veröffentlichungsjahr 2013
Prepublished im Jahr 2012
HGF-Berichtsjahr 2012
ISSN (print) / ISBN 1355-8145
e-ISSN 1466-1268
Zeitschrift Cell Stress and Chaperones
Quellenangaben Band: 18, Heft: 2, Seiten: 183-191 Artikelnummer: , Supplement: ,
Verlag Springer
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Biological and Medical Imaging (IBMI)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-521400-001
PubMed ID 22933182
DOI 10.1007/s12192-012-0369-8
WOS ID WOS:000315415700008
Scopus ID 84878856689
Erfassungsdatum 2012-12-12
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