title: Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic-Induced Apoptosis.
abstract: Malignant gliomas exhibit a high intrinsic resistance against stimuli triggering apoptotic cell death. HSF1 acts as transcription factor upstream of HSP70 and the HSP70 co-chaperone BAG3 that is overexpressed in glioblastoma. To specifically target this resistance mechanism, we applied the selective HSF1 inhibitor KRIBB11 and the HSP70/BAG3 interaction inhibitor YM-1 in combination with the pan-Bcl-2 inhibitor AT-101. Here, we demonstrate that lentiviral BAG3 silencing significantly enhances AT-101-induced cell death and reactivates effector caspase-mediated apoptosis in U251 glioma cells with high BAG3 expression, whereas these sensitizing effects were less pronounced in U343 cells expressing lower BAG3 levels. KRIBB11 decreased protein levels of HSP70, BAG3, and the antiapoptotic Bcl-2 protein Mcl-1, and both KRIBB11 and YM-1 elicited significantly increased mitochondrial dysfunction, effector caspase activity, and apoptotic cell death after combined treatment with AT-101 and ABT-737. Depletion of BAG3 also led to a pronounced loss of cell-matrix adhesion, FAK phosphorylation, and in vivo tumor growth in an orthotopic mouse glioma model. Furthermore, it reduced the plating efficiency of U251 cells in three-dimensional clonogenic assays and limited clonogenic survival after short-term treatment with AT-101. Collectively, our data suggest that the HSF1/HSP70/BAG3 pathway plays a pivotal role for overexpression of prosurvival Bcl-2 proteins and cell death resistance of glioma. They also support the hypothesis that interference with BAG3 function is an effective novel approach to prime glioma cells to anoikis. Mol Cancer Ther; 16(1); 156-68. ©2016 AACR.
authors: Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
authors: Patrick
authors: P
authors: Antonietti
authors: Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
authors: Benedikt
authors: B
authors: Linder
authors: Radiotherapy and Oncology, Goethe University Hospital, Frankfurt am Main, Germany.
authors: Stephanie
authors: S
authors: Hehlgans
authors: Dr. Senckenberg Institute of Neurooncology.
authors: Iris C
authors: IC
authors: Mildenberger
authors: Dr. Senckenberg Institute of Neurooncology.
authors: Michael C
authors: MC
authors: Burger
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe University Hospital, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Simone
authors: S
authors: Fulda
authors: Dr. Senckenberg Institute of Neurooncology.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors: Joachim P
authors: JP
authors: Steinbach
authors: Department of Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
authors: Florian
authors: F
authors: Gessler
authors: Radiotherapy and Oncology, Goethe University Hospital, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors: Franz
authors: F
authors: Rödel
authors: German Cancer Consortium (DKTK), Heidelberg, Germany.|Edinger Institute, Goethe University Hospital, Frankfurt am Main, Germany.
authors: Michel
authors: M
authors: Mittelbronn
authors: Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany. koegel@em.uni-frankfurt.de.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors: Donat
authors: D
authors: Kögel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor; D001713:Biphenyl Compounds / Q000494:pharmacology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006072:Gossypol / Q000031:analogs & derivatives / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D000077022:Survivin; D014157:Transcription Factors / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C501332:ABT-737; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013449:Sulfonamides; D000077022:Survivin; D014157:Transcription Factors; D051020:bcl-X Protein; D006072:Gossypol; C028178:gossypol acetic acid