Induction of HL-60 cell differentiation by the p38 mitogen-activated protein kinase inhibitor SB203580 is mediated through the extracellular signal-regulated kinase signaling pathway.
The pyridinyl imidazole p38 kinase inhibitor, SB203580, was initially used to block inflammatory cytokine synthesis. Here we report that SB203580 by itself could induce human promyeloid leukemic HL-60 cells to differentiate mainly along the granulocytic lineage, as evidenced by cellular morphological changes, and the concurrent expression of cell surface markers CD11b and CD14. This differentiation induction was time and dose dependent. After 12 h exposure to 10 microM SB203580, 12.5% of the cells became CD11b as compared to only 2.6% in untreated control cells. By 96 h, CD11b cells increased to 72.3%, and among them, 26% were CD14. Morphologically, the cells were smaller in size with lower nuclear/cytoplasmic ratio. The nucleus was indented and nucleoli markedly reduced. However, 10 microM SB203580 had little effect on HL-60 cell growth and survival during the first 72 h, but by 96 h the percentage of cells in G1 phase was markedly increased. These effects of SB203580 were not attributable to its inhibition of p38 kinase activity. Instead, the essential kinases in the extracellular signal-regulated kinase (ERK) pathway such as phospho-Raf-1, phospho-MEK1/2, phospho-ERK1/2 and phospho-p90RSK were all elevated dramatically shortly after cells were exposed to SB203580 and lasted for 24 h before declining. Pre-incubation of cells with 20 microM of PD98059 1 h before addition of SB203580 could completely block the expression of differentiation markers. Our results suggest that SB203580-induced differentiation in HL-60 cells was mediated by activation of MEK/ERK signaling. In conclusion, our data have shown that SB203580 possessed biological activities other than inhibition of p38 and these activities could make it a potential candidate as an inducing agent for cell differentiation in the therapeutic treatment of leukemia.
Zhang
Jin-Xia
JX
Bioactive Products Research Group, Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong SAR, China.
Zhuang
Wie-Jian
WJ
Poon
Ka-Hung
KH
Yang
Michael
M
Fong
Wang-Fun
WF
D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580