Butyrate augments interferon-alpha-induced S phase accumulation and persistent tyrosine phosphorylation of cdc2 in...

Interferon-alpha (IFN-alpha) is a clinically useful cytokine for treatment of a variety of cancers, including chronic myelocytic leukaemia (CML). Most CML cells are sensitive to IFN-alpha; however, its biological effects on leukaemic cells are incompletely characterized. Here, we provide evidence that IFN-alpha induces a significant increase in the S phase population in human CML leukaemic cell line, K562, and that the S phase accumulation was augmented by sodium butyrate. In contrast, neither sodium butyrate alone, nor sodium butyrate plus IFN-gamma, affected the cell cycle in K562 cells. These data suggest that the effect of sodium butyrate depended upon IFN-alpha-mediated signalling. The ability of leukaemic cells to exhibit the S phase accumulation after stimulation by IFN-alpha plus sodium butyrate correlated well with persistent tyrosine phosphorylation of cdc2, whereas treatment with IFN-gamma plus sodium butyrate did not affect its phosphorylation levels. Considering that dephosphorylation of cdc2 leads to entry to the M phase, the persistent tyrosine phosphorylation of cdc2 may be associated with the S phase accumulation induced by IFN-alpha and sodium butyrate. In addition, another human CML leukaemic cell line, MEG-01, also showed the S phase accumulation after stimulation with IFN-alpha plus sodium butyrate. Taken together, our studies reveal a novel effect of sodium butyrate on the S phase accumulation and suggest its clinical application for a combination therapy with IFN-alpha, leading to a great improvement of clinical effects of IFN-alpha against CML cells.