Der BCL-2 Inhibitor ABT-199/Venetoclax transaktiviert NOXA und wirkt mit Proteasom-Inhibition bei der Zelltod-Induktion synergistisch

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Dokumentart: Dissertation
Date: 2023-05-11
Language: German
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biochemie
Advisor: Rapaport, Doron (Prof. Dr.)
Day of Oral Examination: 2023-04-04
DDC Classifikation: 500 - Natural sciences and mathematics
Other Keywords: ABT-199
License: Publishing license including print on demand
Order a printed copy: Print-on-Demand
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The development of neoplastic transformations is characterized by persistent proliferation as well as deregulation of the apoptosis signalling pathway. Reduced apoptosis is often caused by overexpression of anti-apoptotic proteins of the BCL 2 protein family. Consequently, these are therapeutic targets, which can be inhibited by specific BCL 2 inhibitors. The specific BCL 2 inhibitor ABT 199 is effective in Multiple Myeloma (MM). Also, the proteasome inhibitor BTZ is an effective and established anti-cancer therapeutic agent approved for therapy of MM and specifically for mantle cell lymphoma (MCL). We recently published that the specific BCL 2 inhibitor ABT 199 in combination with bortezomib (BTZ) is effective in inducing cell death in solid tumours, especially in soft-tissue sarcomas (STS). Further investigation of the identified synergistic apoptosis induction by ABT 199 and BTZ revealed that the mechanism of action is not BTZ-specific but rather mediated by proteasome inhibition in general. The verified key molecules in the ABT 199&PI (proteasome inhibitor)-mediated cell death induction are the effector protein BAX and the BH3-only protein NOXA. Furthermore, the present study shows for the first time that ABT 199 markedly increases PMAIP1/NOXA expression through transcriptional induction. The ABT 199-mediated transcriptional induction of NOXA is predominantly TP53-independent. Analyses of mRNA and protein expression show that ABT-199 induces PMAIP1/NOXA expression through activation of the integrated stress response (ISR). In summary, ABT 199 promotes apoptosis in a twofold manner: i) ABT-199 blocks anti-apoptotic BCL 2 and ii) ABT 199 transactivates NOXA which inhibits anti-apoptotic MCL-1. The identified synergism comes into play when NOXA degradation is additionally inhibited by proteasome inhibition. Since the here revealed and formerly unidentified ABT 199-mediated activation of the ISR and transcriptional induction of NOXA is cell-type unspecific, this mechanism could find application not only in hematopoietic diseases, but also be effective in solid tumour entities.

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