Page 274 - Vitamin D and Cancer

11 Vitamin D and Hematologic Malignancies 261

and PLZF-RARa can bind to VDR in U937 cells and sequester VDR away from
activation of its normal DNA targets localization [81]. Overexpression of VDR over-
comes the block in 1,25(OH) D -stimulated differentiation caused by the fusion pro-
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teins. Of note, PLZF itself can interact directly with VDR, and overexpression of PLZF
can inhibit the 1,25(OH) D -induced differentiation of U937 cells [82].
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The HL-60 and U937 cell lines have been used to attempt to identify early
response genes directly regulated by VDR. Expression of fructose 1,6-biphos-
phatase is up-regulated by 1,25(OH) D in HL-60 cells and peripheral blood mono-
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cytes [83]. cDNA microarray analysis showed that at early times, the putative
oncogenes Dek and Fli-1 were down-regulated and the antiproliferative gene,
BTG1 was up-regulated [84]. After exposure of HL-60 to 1,25(OH) D , similar
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experiments were also noted with the importin and exportin family members which
were down-regulated; these proteins mediate transportation between the nucleus
and the cytoplasm [85]. Also, 1,25(OH) D suppressed the expression of eIF-2 in
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HL-60; this protein is involved in the regulation of protein synthesis [86].
About 160 years ago, sunlight or cod liver oil (both abundant source of vitamin
D) was used as treatment of tuberculosis [87, 88]. In vitro studies suggested that
1,25(OH) D can have a role in activating human macrophages in host defenses
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against mycobacterium tuberculosis (MTB) [89]. Moreover, screening of the
human genome for VDREs showed that the human cathelicidin antimicrobial pep-
tide (CAMP) gene has a VDRE in its promoter; and exposure of myeloid cells to
1,25(OH) D and its analogs induced expression of CAMP [90–92]. Induction of
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CAMP by 1,25(OH) D has been described in hematopoietic cell lines including
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myeloid leukemias (U937, HL60, NB4, K562, KG-1 and THP-1) and primary
hematopoietic cells including leukocytes (monocytes, neutrophils and mac-
rophages) and bone marrow cells of both normal and leukemic individuals [93].
Interestingly, the VDRE for CAMP only appears in a transposable short-inter-
spersed nuclear element (SINE), and these sequences occur only in primates [91].
Induction of this antimicrobial agent by 1,25(OH) D may provide significant pro-
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tection against various microbes.
11.4.2.2 Molecular Mechanisms of Kinase Activities of 1,25(OH) D
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in Leukemic Cells
Data suggest that both the antiproliferative and differentiation-inducing effects of
vitamin D compounds require the modulation of the intracellular kinase pathways,
including PKC, PI3-K, AKT, p38 MAPK and ERK. This modulation probably
occurs too quickly to be attributed to the genomic actions of vitamin D. Activation
of PKC by the phorbol diesters such as TPA, promotes monocyte differentiation of
leukemic cell lines [94, 95]. Differentiation of HL-60 cells in response to
1,25(OH) D is accompanied by increased levels of PKC-b; and this differentiation
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can be inhibited by a specific PKC inhibitor, chelerythrine chloride [96]. Other
vitamin D analogs have been shown to stimulate expression and translocation of
PKC-a and -d during NB4 monocytic differentiation [97].