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Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl)
retinamide and effect of deregulated bcl-2
D Delia, A Aiello, F Formelli, E Fontanella, A Costa, T Miyashita, JC Reed and MA Pierotti
Istituto Nazionale Tumori, European Institute of Oncology, Milan, Italy.
The cancer chemopreventive retinoid N-(4-hydroxyphenyl)-all-trans
retinamide (HPR) was recently shown by us to have antiproliferative and
apoptotic effects on human leukemic cell lines, including those
unresponsive to all-trans retinoic acid (ATRA). We have now characterized
further the process of HPR-induced cell death. We report that inhibitors of
RNA transcription and of protein synthesis, activators of protein kinase C
(PKC), inhibitors of tyrosine kinases, Zn++, and the antioxidants
acetylcysteine, ascorbic acid, alpha- tocopherol, and deferoxamine
suppressed HPR-induced apoptosis. HL60 cells induced toward monocytic
differentiation by 1,25 dihydroxyvitamin- D3 [1,25(OH)2D3], but not those
induced toward the granulocytic differentiation by ATRA, showed reduced
responses to HPR. The transport of HPR by cells with different sensitivity
to the retinoid, however, was similar, even after treatment with the
phorbol ester 12-O- tetradecanoylphorbol-13-acetate (TPA), which induces
unresponsiveness to HPR. The expression of the apoptosis-related genes
bcl-2, p53, and c- myc was examined to determine their role in
HPR-triggered cell death. The levels of bcl-2 mRNA were markedly diminished
by 24 hours of HPR treatment in all cell lines except in the relatively
HPR-insensitive line K422. However, probably because of its long half-life,
bcl-2 protein levels were either unchanged or only slightly decreased.
Downregulation of p53 mRNA was also observed within 24 hours of HPR
exposure in NB4 but not K422 cells, but no changes in the amount of p53
protein were found. Suppression of c-myc transcription was observed in all
cells except K422. The protective role of bcl-2 on cell death by HPR was
investigated in HL60 as well as 697 pre-B leukemia and Jurkat T- acute
lymphocytic leukemia (T-ALL) cells constitutively expressing high levels of
bcl-2 proteins due to gene transfer manipulation. Compared with control
cells, the onset of apoptosis in these cells with deregulated bcl-2
production was delayed by at least 24 hours. These findings establish that
cell death by HPR requires RNA transcription and protein synthesis and is
regulated by the activation of PKC. Although changes in bcl-2, p53, and
c-myc expression are found in cells treated with HPR, the time-course of
these events suggests that HPR- triggered apoptosis is not directly
controlled by these genes. Finally, while ectopic overexpression of bcl-2
does not protect cells from death by HPR, it markedly delays its
onset.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 85,
Issue 2,
pp. 359-367,
01/15/1995
Copyright © 1995 by The American Society of Hematology
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