Abstract
Diallyl disulfide (DADS), the main active component of the cancer fighting allyl sulfides found in garlic, has shown potential as a therapeutic agent in various cancers. Previous studies showed DADS induction of HL‐60 cell differentiation involves down‐regulation of calreticulin (CRT). Here, we investigated the mechanism of DADS‐induced differentiation of human leukaemia cells and the potential involvement of CRT and CCAAT enhancer binding protein‐α (C/EBPα). We explored the expression of CRT and C/EBPα in clinical samples (20 healthy people and 19 acute myeloid leukaemia patients) and found that CRT and C/EBPα expressions were inversely correlated. DADS induction of differentiation of HL‐60 cells resulted in down‐regulated CRT expression and elevated C/EBPα expression. In severe combined immunodeficiency mice injected with HL‐60 cells, DADS inhibited the growth of tumour tissue and decreased CRT levels and increased C/EBPα in vivo. We also found that DADS‐mediated down‐regulation of CRT and up‐regulation of C/EBPα involved enhancement of reactive oxidative species. RNA immunoprecipitation revealed that CRT bound C/EBPα mRNA, indicating its regulation of C/EBPα mRNA degradation by binding the UG‐rich element in the 3′ untranslated region of C/EBPα. In conclusion, the present study demonstrates the C/EBPα expression was correlated with CRT expression in vitro and in vivo and the molecular mechanism of DADS‐induced leukaemic cell differentiation.
Highlights
Acute myeloid leukaemia (AML) is a genetically heterogeneous clonal disorder caused by the buildup of somatic mutations in haematopoietic progenitor cells.[1]
These findings suggest that CRT may be an important factor that regulates CCAAT enhancer binding protein‐α (C/EBPα) in leukaemia differentiation.[18]
flow cytometry (FCM) analysis showed that CD33 expression was reduced in the CRT Small interfering RNA (siRNA)‐transfected HL‐60 cells compared to controls (51.21% vs 93.47%, respectively; Figure 2B)
Summary
Acute myeloid leukaemia (AML) is a genetically heterogeneous clonal disorder caused by the buildup of somatic mutations in haematopoietic progenitor cells.[1]. CRT is a multiprocess calcium buffering chaperone of the endoplasmic reticulum that is essential for numerous cellular functions.[10,11,12] Some studies have identified increased expression of CRT in many tumour tissues or cells.[13] CCAAT enhancer binding protein‐α (C/EBPα) is a basic leucine zipper transcription factor that is crucial for normal neutrophil differentiation.[14] Deregulation of C/EBPα function by genomic mutations, transcriptional, and posttranscriptional suppression, or phosphorylation‐dependent inactivation is a common event in subgroups of AML patients.[15,16] Previous studies have shown that in some leukaemic cells, the inhibition of C/EBPα transcription and translation level is closely related to CRT.[17] The down‐ regulation of CRT by siRNA can increase the expression of C/EBPα These findings suggest that CRT may be an important factor that regulates C/EBPα in leukaemia differentiation.[18]. These findings may lead to a better understanding of the molecular mechanisms of the down‐regulation of CRT in DADS‐induced differentiation of leukaemia cells and will provide essential knowledge for the development of differentiation inducers to treat leukaemia
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