• Treffer 3 von 4
Zurück zur Trefferliste

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.

Volltext Dateien herunterladen

Metadaten exportieren

Metadaten
Verfasserangaben:Irina Kiprianova, Janina RemyGND, Nelli Milosch, Isabelle Vanessa Mohrenz, Volker SeifertORCiD, Achim AignerORCiDGND, Donat KögelORCiD
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
Titel des übergeordneten Werkes (Englisch):Neoplasia
Verlag:Stockton Press
Verlagsort:Basingstoke
Dokumentart:Wissenschaftlicher Artikel
Sprache:Englisch
Jahr der Fertigstellung:2015
Datum der Erstveröffentlichung:18.08.2015
Veröffentlichende Institution:Universitätsbibliothek Johann Christian Senckenberg
Datum der Freischaltung:22.07.2019
Jahrgang:17
Ausgabe / Heft:7
Seitenzahl:10
Erste Seite:564
Letzte Seite:573
Bemerkung:
© 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
Institute:Medizin / Medizin
DDC-Klassifikation:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Lizenz (Deutsch):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0