Diallyl disulfide down-regulates calreticulin and promotes C/EBPα expression in differentiation of human leukaemia cells.
J Cell Mol Med. 2019 01 ;23(1):194-204. Epub 2018 Nov 5. PMID: 30394654
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 expressionand 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 wascorrelated with CRT expression in vitro and in vivo and the molecular mechanism of DADS-induced leukaemic cell differentiation.