Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 90, Issue 2, Pages 235-247Publisher
WILEY
DOI: 10.1189/jlb.0109025
Keywords
retinoic acid receptor; endothelial cells; adhesion
Categories
Funding
- Ministry of Health, Labor, and Welfare of Japan
- Takeda Science Foundation
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- [17790545]
- [16590898]
- [17390245]
- Grants-in-Aid for Scientific Research [22890014, 22591006] Funding Source: KAKEN
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ATRA and a synthetic RAR agonist tamibarotene (Am80) induce granulocytic differentiation of human acute leukemia HL-60 cells and have been used in antineoplastic therapy. ATRA induces CD38 antigen during HL-60 cell differentiation, which interacts with CD31 antigen on the vascular EC surface and may induce disadvantages in the therapy. We here examined the mechanisms of the ATRA-mediated CD38 induction and compared the difference between ATRA-and tamibarotene-mediated induction. Tamibarotene-induced HL-60 cell adhesion to ECs was 38% lower than ATRA, and NB4 cell adhesion to ECs by tamibarotene was equivalent to ATRA, which induced CD38 gene transcription biphasically in HL-60 cells, the early-phase induction via DR-RARE containing intron 1, and the delayed-phase induction via RARE lacking the 5'-flanking region. In contrast to ATRA, tamibarotene induced only the early-phase induction, resulting in its lower CD38 induction than ATRA. A PKC delta inhibitor, rottlerin, and siRNA-mediated PKC delta knockdown suppressed the ATRA-induced CD38 promoter activity of the 5'-flanking region, whereas a RAR antagonist, LE540, or RAR knockdown did not affect it. Cycloheximide and rottlerin suppressed the delayed-phase induction of CD38 expression by ATRA but did not affect the early-phase induction. Moreover, ATRA, but not tamibarotene, induced PKC delta expression without affecting its mRNA stability. The diminished effect of tamibarotene on CD38-mediated HL-60 cell adhesion to ECs compared with ATRA is likely a result of the lack of its delayed-phase induction of CD38 expression, which may be advantageous in antineoplastic therapy. J. Leukoc. Biol. 90: 235-247; 2011.
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