title: Radiosensitization of wildtype p53 cancer cells by the MDM2-inhibitor PXN727 is associated with altered heat shock protein 70 (Hsp70) levels.
abstract: 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.
authors.affiliation: Department of Radiotherapy and Radiooncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schilling
authors.forename: Michael
authors.initials: M
authors.lastname: Düwel
authors.forename: Michael
authors.initials: M
authors.lastname: Molls
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects* / Q000528:radiation effects; D045325:HCT116 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000633:toxicity; D010879:Piperazines / Q000633:toxicity; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000528:radiation effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D018840:HSP70 Heat-Shock Proteins; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2