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Targeted inhibition of protein synthesis renders cancer cells vulnerable to apoptosis by unfolded protein response
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Targeted inhibition of protein synthesis renders cancer cells vulnerable to apoptosis by unfolded protein response
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Journal Article
Targeted inhibition of protein synthesis renders cancer cells vulnerable to apoptosis by unfolded protein response
2023
Overview
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.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/31
/ 13/89
/ 631/67
/ 64/60
/ 82/29
/ 82/80
/ Acute lymphoblastic leukemia
/ Animals
/ Biomedical and Life Sciences
/ Humans
/ Lymphoma
/ Mice
/ Protein Serine-Threonine Kinases
/ Proteins
