title: Pioglitazone, a PPAR-gamma ligand, exerts cytostatic/cytotoxic effects against cancer cells, that do not result from inhibition of proteasome.
abstract: Thiazolidinediones are oral antidiabetic agents that activate peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and exert potent antioxidant and anti-inflammatory properties. It has also been shown that PPAR-gamma agonists induce G0/G1 arrest and apoptosis of malignant cells. Some of these effects have been suggested to result from inhibition of proteasome activity in target cells. The aim of our studies was to critically evaluate the cytostatic/cytotoxic effects of one of thiazolidinediones (pioglitazone) and its influence on proteasome activity. Pioglitazone exerted dose-dependent cytostatic/cytotoxic effects in MIA PaCa-2 cells. Incubation of tumor cells with pioglitazone resulted in increased levels of p53 and p27 and decreased levels of cyclin D1. Accumulation of polyubiquitinated proteins within cells incubated with pioglitazone suggested dysfunction of proteasome activity. However, we did not observe any influence of pioglitazone on the activity of isolated proteasome and on the proteolytic activity in lysates of pioglitazone-treated MIA PaCa-2 cells. Further, treatment with pioglitazone did not cause an accumulation of fluorescent proteasome substrates in transfected HeLa cells expressing unstable GFP variants. Our results indicate that pioglitazone does not act as a direct or indirect proteasome inhibitor.
authors.affiliation: Department of Immunology, Center of Biostructure Research, The Medical University of Warsaw, Warszawa, Poland. pmroovka@ib.amwaw.edu.pl
authors.forename: Piotr
authors.initials: P
authors.lastname: Mrówka
authors.forename: Eliza
authors.initials: E
authors.lastname: Głodkowska
authors.forename: Izabela
authors.initials: I
authors.lastname: Młynarczuk-Biały
authors.forename: Lukasz
authors.initials: L
authors.lastname: Biały
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kuckelkorn
authors.forename: Dominika
authors.initials: D
authors.lastname: Nowis
authors.forename: Marcin
authors.initials: M
authors.lastname: Makowski
authors.forename: Magdalena
authors.initials: M
authors.lastname: Legat
authors.forename: Jakub
authors.initials: J
authors.lastname: Gołab
mesh_terms: D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D054697:Cytostatic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D045162:Thiazolidinediones / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D054697:Cytostatic Agents; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D045162:Thiazolidinediones; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D046988:Proteasome Endopeptidase Complex; D000077205:Pioglitazone