Cotylenin A, which has been isolated as a
plant growth regulator, potently induces the differentiation of human
myeloid leukemia cells. Treatment of HL-60 cells with a combination of
transforming growth factor (
TGF)-beta and 1alpha, 25-dihydroxyvitamin D(3) (VD3) resulted in increased differentiation compared to separate treatments, but
TGF-beta did not affect the
cotylenin A-induced differentiation of HL-60 cells. It is possible that the signal transduction pathway used by
cotylenin A for inducing the differentiation of
leukemia cells is the same as that used by
TGF-beta. However,
cotylenin A did not affect the expression of TGF superfamily or Smad genes in HL-60 cells. Treatment with neutralizing anti-
TGF-beta antibody or an inhibitor of
TGF-beta signaling did not inhibit
cotylenin A-induced differentiation, although VD3-induced differentiation was significantly suppressed by these treatments. The subcellular distribution of Smad3 was also unaffected by
cotylenin A. These results suggest that the
cotylenin A-induced differentiation of
leukemia cells is independent of the
TGF-beta signaling system, although
TGF-beta acts as an autocrine mediator of the growth arrest and differentiation of
leukemia cells induced by VD3 and other inducers.