دورية أكاديمية
The BCL-2 inhibitor ABT-199/venetoclax synergizes with proteasome inhibition via transactivation of the MCL-1 antagonist NOXA
| العنوان: | The BCL-2 inhibitor ABT-199/venetoclax synergizes with proteasome inhibition via transactivation of the MCL-1 antagonist NOXA |
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| المؤلفون: | Sandra Weller, Astrid Toennießen, Benjamin Schaefer, Tobias Beigl, Alina Muenchow, Kathrin Böpple, Ute Hofmann, Bernhard F. Gillissen, Walter E. Aulitzky, Hans-Georg Kopp, Frank Essmann |
| المصدر: | Cell Death Discovery, Vol 8, Iss 1, Pp 1-12 (2022) |
| بيانات النشر: | Nature Publishing Group, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens LCC:Cytology |
| مصطلحات موضوعية: | Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671 |
| الوصف: | Abstract Enhanced expression of anti-apoptotic B-cell lymphoma 2 (BCL-2) protein is frequent in cancer. Targeting of BCL-2 with the specific inhibitor ABT-199 (Venetoclax) has significant clinical activity in malignant diseases such as chronic lymphocytic leukemia and multiple myeloma. The small molecule drug ABT-199 mimics the pro-apoptotic BCL-2 homology domain 3 of BH3-only proteins and blocks the hydrophobic BC-groove in BCL-2. We have previously shown that ABT-199 synergizes with the proteasome inhibitor (PI) bortezomib in soft tissue sarcoma derived cells and cell lines to induce apoptosis. Synergistic apoptosis induction relies on the pore-forming effector BAX and expression of the pro-apoptotic BH3-only protein NOXA. Bortezomib augments expression of NOXA by blocking its proteasomal degradation. Interestingly, shown here for the first time, expression of NOXA is strongly enhanced by ABT-199 induced integrated stress response (ISR). ISR transcription factors ATF3 & ATF4 mediate transactivation of the BH3-only protein NOXA which specifically inhibits the anti-apoptotic MCL-1. Thus, NOXA potentiates the efficacy of the BCL-2 inhibitor ABT-199 by simultaneous inhibition of MCL-1. Hence, ABT-199 has a double impact by directly blocking anti-apoptotic BCL-2 and inhibiting MCL-1 via transactivated NOXA. By preventing degradation of NOXA PIs synergize with ABT-199. Synergism of ABT-199 and PIs therefore occurs on several, previously unexpected levels. This finding should prompt clinical evaluation of combinatorial regimens in further malignancies. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2058-7716 |
| العلاقة: | https://doaj.org/toc/2058-7716Test |
| DOI: | 10.1038/s41420-022-01009-1 |
| الوصول الحر: | https://doaj.org/article/25b403ed7a8d4d12935b61caf6d80df9Test |
| رقم الانضمام: | edsdoj.25b403ed7a8d4d12935b61caf6d80df9 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 20587716 |
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| DOI: | 10.1038/s41420-022-01009-1 |