Inhibition of proteasome activity sensitizes human granulosa tumor cells to TRAIL-induced cell death.
Human granulosa tumor cell (GCT) lines (KGN and COV434) were utilized to establish the combinatorial effects of TRAIL treatment and a proteasome inhibitor on cell viability, in vitro. TRAIL induced a slight, but consistent, decrease in viability for both cell lines, and pharmacologic inhibition of proteasome activity, using Z-LLF-CHO (Z-LLF), synergistically enhanced TRAIL-induced loss of viability. This enhanced sensitization was associated with the up-regulation of a TRAIL receptor, DR5, and pro-apoptotic Bax. Targeted reduction of p53 expression revealed that the ability of Z-LLF to enhance DR5 and Bax expression occurs independent of p53 activity. These studies underscore the potential to develop targeted treatments for GCTs using established cell lines.
Woods
Dori C
DC
Department of Biological Sciences and the Walther Cancer Research Center, The University of Notre Dame, Notre Dame, IN 46556, USA.
Liu
Han-Ken
HK
Nishi
Yoshihiro
Y
Yanase
Toshihiko
T
Johnson
A L
AL
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006106:Granulosa Cell Tumor / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C494826:BAX protein, human; D009842:Oligopeptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C077180:N-benzyloxycarbonyl-leucyl-leucyl-phenylalaninal; D045304:Cytochromes c; C505530:CASP8 protein, human; D053181:Caspase 8; D046988:Proteasome Endopeptidase Complex