Inhibition of protein disulfide isomerase induces differentiation of acute myeloid leukemia cells.
PBN-AR
Instytucja
Instytut Biochemii i Biofizyki Polskiej Akademii Nauk
Informacje podstawowe
Główny język publikacji
EN
Czasopismo
Haematologica-The Hematology Journal (40pkt w roku publikacji)
ISSN
0390-6078
EISSN
1592-8721
Wydawca
FERRATA STORTI FOUNDATION
DOI
URL
Rok publikacji
2018
Numer zeszytu
11
Strony od-do
1843-1852
Numer tomu
103
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Słowa kluczowe
PL
brak
Open access
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Wersja ostateczna autora
Licencja otwartego dostępu
Creative Commons — Uznanie autorstwa-Niekomercyjne
Czas opublikowania w otwartym dostępie
Razem z publikacją
Data udostępnienia w sposób otwarty
2018-07-12
Streszczenia
Język
EN
Treść
A cute myeloid leukemia is a malignant disease of immature myeloid cells. Despite significant therapeutic effects of differentiation-inducing agents in some acute myeloid leukemia subtypes, the disease remains incurable in a large fraction of patients. Here we show that SK053, a thioredoxin inhibitor, induces differentiation and cell death of acute myeloid leukemia cells. Considering that thioredoxin knock-down with short hairpin RNA failed to exert antiproliferative effects in one of the acute myeloid leukemia cell lines, we used a biotin affinity probe-labeling approach to identify potential molecular targets for the effects of SK053. Mass spectrometry of proteins precipitated from acute myeloid leukemia cells incubated with biotinylated SK053 used as a bait revealed protein disulfide isomerase as a potential binding partner for the compound. Biochemical, enzymatic and functional assays using fluorescence lifetime imaging confirmed that SK053 binds to and inhibits the activity of protein disulfide isomerase. Protein disulfide isomerase knockdown with short hairpin RNA was associated with inhibition of cell growth, increased CCAAT enhancer-binding protein α levels, and induction of differentiation of HL-60 cells. Molecular dynamics simulation followed by the covalent docking indicated that SK053 binds to the fourth thioredoxin-like domain of protein disulfide isomerase. Differentiation of myeloid precursor cells requires the activity of CCAAT enhancer-binding protein α, the function of which is impaired in acute myeloid leukemia cells through various mechanisms, including translational block by protein disulfide isomerase. SK053 increased the levels of CCAAT enhancer-binding protein α and upregulated mRNA levels for differentiation-associated genes. Finally, SK053 decreased the survival of blasts and increased the percentage of cells expressing the maturation-associated CD11b marker in primary cells isolated from bone marrow or peripheral blood of patients with acute myeloid leukemia. Collectively, these results provide a proof-of-concept that protein disulfide isomerase inhibition has potential as a therapeutic strategy for the treatment of acute myeloid leukemia and for the development of small-molecule inhibitors of protein disulfide isomerase.
Inne
System-identifier
PX-5beede32d5dea02141b2fe6d
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