Proteasome inhibition overcomes the resistance of renal cell carcinoma cells against the PPARgamma ligand troglitazone.
In order to analyze the effects of peroxisome proliferator-activated receptor-gamma (PPARgamma) activation on renal cell carcinomas we utilized several cell lines that were treated with the high affinity PPARgamma agonist, troglitazone. Incubation of RCC cells with troglitazone resulted in reduced secretion of growth factors that was due to the inhibition of MAP kinase signaling and reduced nuclear localized expression of relB and HIF1alpha. Interestingly, the cell lines used showed a different sensitivity towards apoptosis induction that did not correlate with the inhibition of growth factors or expression of pro- and antiapoptotic molecules. To overcome this resistance the cells were treated with a combination of troglitazone and the proteasome inhibitor, bortezomib. The combination of both compounds induced apoptosis even in cells resistant to both agents alone, due to increased induction of ER-stress and caspase-3 mediated cell death.
von Schwarzenberg
K
K
Department of Hematology and Oncology, University of Bonn, Wilhelmstr. 35-37, 53111 Bonn, Germany.
Held
S A E
SA
Schaub
A
A
Brauer
K M
KM
Bringmann
A
A
Brossart
P
P
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D043925:Angiogenesis Inducing Agents; D000970:Antineoplastic Agents; D001897:Boronic Acids; D002839:Chromans; D016207:Cytokines; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D047495:PPAR gamma; D061988:Proteasome Inhibitors; D011719:Pyrazines; D045162:Thiazolidinediones; D000069286:Bortezomib; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; D000077288:Troglitazone