Targeted inhibition of protein synthesis renders cancer cells vulnerable to apoptosis by unfolded protein response

Gsottberger F, Meier C, Ammon AM, Parker S, Wendland K, George R, Petkovic S, Mellenthin L, Emmerich C, Lutzny-Geier G, Metzler M, Mackensen A, Chandramohan V, Müller F (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Cell Death & Disease Nature Publishing Group: Open Access Journals - Option B / Nature Publishing Group

Book Volume: 14

Article Number: 561

Journal Issue: 8

DOI: 10.1038/s41419-023-06055-w

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.

Authors with CRIS profile

Franziska Gsottberger Department of Medicine 5 – Haematology and Oncology Christina Meier Lehrstuhl für Innere Medizin V Anna-Maria Ammon Department of Medicine 5 – Haematology and Oncology Kerstin Wendland Department of Medicine 5 – Haematology and Oncology Rebekka George Lehrstuhl für Innere Medizin V Gloria Lutzny-Geier Department of Medicine 5 – Haematology and Oncology Markus Metzler Professur für Kinder- und Jugendmedizin mit dem Schwerpunkt Pädiatrische Onkologie und Hämatologie Andreas Mackensen Lehrstuhl für Innere Medizin V Fabian Müller Department of Medicine 5 – Haematology and Oncology

Involved external institutions

Duke University Medical Center US United States (USA) (US)

How to cite

APA:

Gsottberger, F., Meier, C., Ammon, A.-M., Parker, S., Wendland, K., George, R.,... Müller, F. (2023). Targeted inhibition of protein synthesis renders cancer cells vulnerable to apoptosis by unfolded protein response. Cell Death & Disease, 14(8). https://doi.org/10.1038/s41419-023-06055-w

MLA:

Gsottberger, Franziska, et al. "Targeted inhibition of protein synthesis renders cancer cells vulnerable to apoptosis by unfolded protein response." Cell Death & Disease 14.8 (2023).

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