| Autor: |
Franziska Gsottberger, Christina Meier, Anna Ammon, Scott Parker, Kerstin Wendland, Rebekka George, Srdjan Petkovic, Lisa Mellenthin, Charlotte Emmerich, Gloria Lutzny-Geier, Markus Metzler, Andreas Mackensen, Vidyalakshmi Chandramohan, Fabian Müller |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Cell Death and Disease, Vol 14, Iss 8, Pp 1-13 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-4889 |
| DOI: |
10.1038/s41419-023-06055-w |
| Popis: |
Abstract Cellular stress responses including the unfolded protein response (UPR) decide over the fate of an individual cell to ensure survival of the entire organism. During physiologic UPR counter-regulation, protective proteins are upregulated to prevent cell death. A similar strategy induces resistance to UPR in cancer. Therefore, we hypothesized that blocking protein synthesis following induction of UPR substantially enhances drug-induced apoptosis of malignant cells. In line, upregulation of the chaperone BiP was prevented by simultaneous arrest of protein synthesis in B cell malignancies. Cytotoxicity by immunotoxins—approved inhibitors of protein synthesis—was synergistically enhanced in combination with UPR-inducers in seven distinct hematologic and three solid tumor entities in vitro. Synergistic cell death depended on mitochondrial outer membrane permeabilization via BAK/BAX, which correlated with synergistic, IRE1α-dependent reduction of BID, accompanied by an additive fall of MCL-1. The strong synergy was reproduced in vivo against xenograft mouse models of mantle cell lymphoma, Burkitt’s lymphoma, and patient-derived acute lymphoblastic leukemia. In contrast, synergy was absent in blood cells of healthy donors suggesting a tumor-specific vulnerability. Together, these data support clinical evaluation of blocking stress response counter-regulation using inhibitors of protein synthesis as a novel therapeutic strategy. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
Full text from SpringerLink