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,25(OH)2-Vitamin D3, 1,24(OH)2-22-Ene-24-Cyclopropyl-Vitamin D3 and 1,25(OH)2-Lumisterol3 Prime NB4 Leukemia Cells for Monocytic Differentiation via Nongenomic Signaling Pathways, Involving Calcium and Calpain1
Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada, N1G 2W1
Address all correspondence and requests for reprints to: Kelly A. Meckling-Gill, Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada, N1G 2W1. E-mail: kmeckling.ns{at}APS.UoGuelph.ca
Side-chain modified vitamin D analogs including
20-Epi-22-oxa-24a,26a,27a-trihomo-1
,25-dihydroxyvitamin
D3 (KH1060), and
1,24-dihydroxy-22-ene-24-cyclopropyl-vitamin D3 (MC903)
were originally designed to aid in the treatment of hyperproliferative
disorders including psoriasis and cancer. Here we demonstrate that
these analogs, as well as the 6-cis-locked conformer,
1,25-dihydroxy-lumisterol3 (JN) prime NB4 cells for
monocytic differentiation. Previously, the action of MC903 and KH1060
was presumed to be mediated by the nuclear vitamin D receptor
(VDRnuc). Differentiation in response to all analogs was
shown to be inhibited by 1ß,25-dihydroxyvitamin D3 (HL),
the antagonist to the nongenomic activities of 1,25D3.
These data suggest that although MC903 and KH1060 may bind the
VDRnuc, that the differentiative activities of these agents
requires nongenomic signaling pathways. Here we show that
1,25(OH)2-d5-previtamin D3 (HF),
JN, KH1060, and MC903 induce expression of PKC and PKC
and
translocation of both isoforms to the particulate fraction, and PKC
to the nuclear fraction. The full differentiation response with
combinations of analogs and TPA was inhibited 50% by the mem-brane
permeable Ca2+ chelator,
1,2-bis(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM) or
calpain inhibitor I. These data demonstrate that intracellular free
calcium and the calcium-dependent protease, calpain play critical roles
in monocytic differentiation. Intracellular calcium appears to be most
critical in the 1,25D3-priming stage of differentiation,
while calpain is essential in the TPA maturation response.
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