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7 Induction of Differentiation in Cancer Cells by Vitamin D 163

Interestingly, 1,25D has also been reported to have a negative effect on
differentiation, as it inhibits IL-4/GM-CSF-induced differentiation of human mono-
cytes into dendritic cells, and this contributes to 1,25D immunosuppressive activity
[197, 198]. The data also suggested that 1,25D specifically downregulates the
expression of CSF-1, and promoted spontaneous apoptosis of mature dendritic cells,
further demonstrating the pleiotropic effects of 1,25D and the cell type-specificity of
the outcomes.

7.4 Conclusion

The signaling pathways presented here are shown to control the activity of several
transcription factors, such as the ubiquitous AP-1 complex, the nuclear receptor
VDR, and the lineage-determining C/EBP family of transcription factors. While
these clearly play a role in 1,25D-induced differentiation of HL60 cells, there may
be redundancy of important cellular regulators, and other pathways and transcription
factors are likely to be involved. The initial steps that activate the differentiation-
inducing actions of 1,25D are not entirely clear, and while cell membrane-associated
events have a role, these events are not necessarily rapid but are sustained. It is likely
that microRNAs will be found to further control or modulate 1,25D signaling, as
retinoic acid-induced differentiation of NB4 AML cells has been shown to be asso-
ciated with the upregulation of a number of microRNAs, and the downregulation of
microRNA 181b [199]. Thus, extensive additional investigations are warranted to
provide a basis for the design of improved therapies of leukemia and solid tumors.

Acknowledgments We thank Drs. Michael Danilenko, David Goldberg, and Ewa Marcinkowska
for comments on the manuscript, and Ms. Vivienne Lowe for expert secretarial assistance. The
author’s experimental work was supported by grants from the National Cancer Institute RO1-CA
44722–18 and RO1-CA 117942–01, and from the Polish Ministry of Science and Higher
Education, grant No. 2622/P01/2006/31.

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