title: Hypoxia enhances the senescence effect of bortezomib--the proteasome inhibitor--on human skin fibroblasts.
abstract: The 26S proteasome inhibitor, bortezomib, selectively induces apoptosis in some cancer cells. However, the nature of its selectivity remains unknown. The study presented here provides novel information on cellular effects of bortezomib in normal fibroblasts. We have found that in normoxic conditions the percent of apoptotic cells did not change significantly, independently on incubation time and examined concentration of bortezomib (25 nmol/L or 50 nmol/L). In hypoxic conditions we did not observe any effect of bortezomib on apoptosis of fibroblasts incubated for 24 h and 48 h in comparison to control. Only in the case of fibroblasts incubated for 12 hours in hypoxia significant increase in apoptosis, dependent on concentration of bortezomib, was observed. Our study has shown that bortezomib causes a time-dependent increase in senescence of normal fibroblasts, especially of these incubated in hypoxic conditions. Moreover, we demonstrated that oxygen regulated protein 150 (ORP150) expression was induced in fibroblasts in hypoxia conditions only, suggesting that this protein may play an important role in the cytoprotective response to environmental stress.
authors.affiliation: Department of Pharmaceutical Biochemistry, Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Krętowski
authors.affiliation: Department of Pharmaceutical Biochemistry, Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Borzym-Kluczyk
authors.affiliation: Department of Pharmaceutical Biochemistry, Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok, Poland.
authors.forename: Marzanna
authors.initials: M
authors.lastname: Cechowska-Pasko
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D012867:Skin / Q000166:cytology*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D001897:Boronic Acids; C497442:HIF1A protein, human; D018840:HSP70 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D061988:Proteasome Inhibitors; D011719:Pyrazines; C050087:oxygen-regulated proteins; D000069286:Bortezomib; D001616:beta-Galactosidase