Sorafenib sensitizes glioma cells to the BH3 mimetic ABT-737 by targeting MCL1 in a STAT3-dependent manner
- 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.
Author: | Irina Kiprianova, Janina RemyGND, Nelli Milosch, Isabelle Vanessa Mohrenz, Volker SeifertORCiD, Achim AignerORCiDGND, Donat KögelORCiD |
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URN: | urn:nbn:de:hebis:30:3-504949 |
DOI: | https://doi.org/10.1016/j.neo.2015.07.003 |
ISSN: | 1476-5586 |
ISSN: | 1522-8002 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/26297434 |
Parent Title (English): | Neoplasia |
Publisher: | Stockton Press |
Place of publication: | Basingstoke |
Document Type: | Article |
Language: | English |
Year of Completion: | 2015 |
Date of first Publication: | 2015/08/18 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2019/07/22 |
Volume: | 17 |
Issue: | 7 |
Page Number: | 10 |
First Page: | 564 |
Last Page: | 573 |
Note: | © 2015 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. Thisis an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
HeBIS-PPN: | 452224632 |
Institutes: | Medizin / Medizin |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0 |