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

Abstract

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.