Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition-Associated Checkpoint Abrogation

Signaling via the MET receptor tyrosine kinase has been implicated in crosstalk with cellular responses to DNA damage. Our group previously demonstrated that MET inhibition in tumor cells with deregulated MET activity results in radiosensitization via downregulation of the ATR-CHK1-CDC25 pathway, a major signaling cascade responsible for intra-S and G2/M cell cycle arrest following DNA damage. Here we aimed at studying the potential therapeutic application of ionizing radiation in combination with a MET inhibitor, EMD-1214063, in p53-deficient cancer cells that harbor impaired G1/S checkpoint regulation upon DNA damage. We hypothesized that upon MET inhibition, p53-deficient cells would bypass both G1/S and G2/M checkpoints, promoting premature mitotic entry with substantial DNA lesions and cell death in a greater extent than p53-proficient cells. Our data suggest that p53-deficient cells are more susceptible to EMD-1214063 and combined treatment with irradiation than wildtype p53 lines as inferred from elevated γH2AX expression and increased cytotoxicity. Furthermore, cell cycle distribution profiling indicates constantly lower G1 and higher G2/M population as well as higher expression of a mitotic marker p-histone H3 following the dual treatment in p53 knockdown isogenic variant, compared to the parental counterpart. IMPLICATIONS The concept of MET inhibition-mediated radiosensitization enhanced by p53 deficiency is of high clinical relevance, since p53 is frequently mutated in numerous types of human cancer. The current data point for a therapeutic advantage for an approach combining MET targeting along with DNA damaging agents for MET positive/p53 negative tumors.

Diomedis Grammatici Opvs, Ab Ioanne Caesario, ita emendatum, scholijsq[ue] illustratum, ut nulla porrò labes insideat. Item Donati De Octo Orationis partibus, & barbarismo libellus, ab eodem recognitus. Cum Indice

Fingerprint nach Ex. der HAAB Weimar und der UB Frankfurt

Ms. Praed. 140 - Quaestiones in Sententiarum librum primum et secundum

Vorbesitzer: Dominikanerkloster Frankfurt am Main

Ms. Praed. 164 - Auctoritates Aristotelis et aliorum philosophorum

Vorbesitzer: Dominikanerkloster Frankfurt am Main

Flugschr. G. Fr. 2154 - Divisiones decem nationum totius christianitatis

Vorbesitzer: Gustav Freytag

Inc. gr. fol. 18 (Ausst. 170) - Chronica

Vorbesitzer: Hinrick Garlop (Besitzvermerk Iv); Zacharias Konrad von Uffenbach (Exlibris im Vorderdeckel);

Ains Judenbüechlins verlegung: darin ain Christ

gantzer Christenhait zu schmach / will es geschehe den Juden unrecht in bezichtigung der Christen kinder mordt [[Elektronische Ressource]] / Durch Doctor Joh. Ecken

(Table S1) Diatom species richness from the Early Pleistocene to present

The extent to which the spatial distribution of marine planktonic microbes is controlled by local environmental selection or dispersal is poorly understood. Our ability to separate the effects of these two biogeographic controls is limited by the enormous environmental variability both in space and through time. To circumvent this limitation, we analyzed fossil diatom assemblages over the past ~1.5 million years from the world oceans and show that these eukaryotic microbes are not limited by dispersal. The lack of dispersal limitation in marine diatoms suggests that the biodiversity at the microbial level fundamentally differs from that of macroscopic animals and plants for which geographic isolation is a common component of speciation.