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Targeting the endoplasmic reticulummitochondria interface sensitizes leukemia cells to cytostatics.
Haematologica 104, 546-555 (2019)
Combination chemotherapy has proven to be a favorable strategy to treat acute leukemia. However, the introduction of novel compounds remains challenging and is hindered by a lack of understanding of their mechanistic interactions with established drugs. In the present study, we demonstrate a highly increased response of various acute leukemia cell lines, drug-resistant cells and patient-derived xenograft cells by combining the recently introduced protein disulfide isomerase inhibitor PS89 with cytostatics. In leukemic cells, a pro-teomics-based target fishing approach revealed that PS89 affects a whole network of endoplasmic reticulum homeostasis proteins. We elucidate that the strong induction of apoptosis in combination with cytostatics is orchestrated by the PS89 target B-cell receptor-associated protein 31, which transduces apoptosis signals at the endoplasmic reticulum-mitochondria interface. Activation of caspase-8 and cleavage of B-cell receptor-associated protein 31 stimulate a pro-apoptotic crosstalk including release of calcium from the endoplasmic reticulum and an increase in the levels of reactive oxygen species resulting in amplification of mitochondrial apoptosis. The findings of this study promote PS89 as a novel chemosensitizing agent for the treatment of acute leukemia and uncovers that targeting the endoplasmic reticulum-mitochondrial network of cell death is a promising approach in combination therapy.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Acute Myeloid Leukemia ; Adult Acute Lymphoblastic Leukemia ; Molecular Pharmacology ; Pediatric Acute Lymphoblastic Leukemia; Protein Disulfide-isomerase; Induced Apoptosis; Resistance; Network; Inhibitor; Mechanisms; Reveals; Redox
ISSN (print) / ISBN
0390-6078
e-ISSN
1592-8721
Quellenangaben
Volume: 104,
Issue: 3,
Pages: 546-555
Publisher
Ferrata Storti Foundation
Publishing Place
Via Giuseppe Belli 4, 27100 Pavia, Italy
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)