title: Sorafenib Sensitizes Glioma Cells to the BH3 Mimetic ABT-737 by Targeting MCL1 in a STAT3-Dependent Manner.
abstract: The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is overactivated in malignant glioma and plays a key role in promoting cell survival, thereby increasing the acquired apoptosis resistance of these tumors. Here we investigated the STAT3/myeloid cell leukemia 1 (MCL1) signaling pathway as a target to overcome the resistance of glioma cells to the Bcl-2-inhibiting synthetic BH3 mimetic ABT-737. Stable lentiviral knockdown of MCL1 sensitized LN229 and U87 glioma cells to apoptotic cell death induced by single-agent treatment with ABT-737 which was associated with an early activation of DEVDase activity, cytochrome c release, and nuclear apoptosis. Similar sensitizing effects were observed when ABT-737 treatment was combined with the multikinase inhibitor sorafenib which effectively suppressed levels of phosphorylated STAT3 and MCL1 in MCL1-proficient LN229 and U87 glioma cells. In analogous fashion, these synergistic effects were observed when we combined ABT-737 with the STAT3 inhibitor WP-1066. Lentiviral knockdown of the activating transcription factor 5 combined with subsequent quantitative polymerase chain reaction analysis revealed that sorafenib-dependent suppression of MCL1 occurred at the transcriptional level but did not depend on activating transcription factor 5 which previously had been proposed to be essential for MCL1-dependent glioma cell survival. In contrast, the constitutively active STAT3 mutant STAT3-C was able to significantly enhance MCL1 levels under sorafenib treatment to retain cell survival. Collectively, these data demonstrate that sorafenib targets MCL1 in a STAT3-dependent manner, thereby sensitizing glioma cells to treatment with ABT-737. They also suggest that targeting STAT3 in combination with inducers of the intrinsic pathway of apoptosis may be a promising novel strategy for the treatment of malignant glioma.
authors: Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
authors: Irina
authors: I
authors: Kiprianova
authors: Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
authors: Janina
authors: J
authors: Remy
authors: Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
authors: Nelli
authors: N
authors: Milosch
authors: Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
authors: Isabelle V
authors: IV
authors: Mohrenz
authors: Dept. of Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany.
authors: Volker
authors: V
authors: Seifert
authors: Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany.
authors: Achim
authors: A
authors: Aigner
authors: Experimental Neurosurgery, Goethe University Hospital, Frankfurt am Main, Germany. Electronic address: koegel@em.uni-frankfurt.de.
authors: Donat
authors: D
authors: Kögel
mesh_terms: D051696:Activating Transcription Factors / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000473:pathology*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009596:Nitrophenols / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C501332:ABT-737; C507532:ATF5 protein, human; D051696:Activating Transcription Factors; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D020032:Tyrphostins; C519885:WP1066; D009536:Niacinamide; D045304:Cytochromes c; D000077157:Sorafenib; D010447:Peptide Hydrolases; C108711:DEVDase