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(Journal of Leukocyte Biology. 2001;69:794-802.)
© 2001 by Society for Leukocyte Biology

Modulation of death receptor-mediated apoptosis in differentiating human myeloid leukemia HL-60 cells

Jan Vondráek^*, Michael A. Sheard², Pavel Krejí³, Kateina Minksová^*, Jiina Hofmanová^* and Alois Kozubík^*

^* Institute of Biophysics,
Masaryk Memorial Cancer Institute, and
Laboratory of Molecular Embryology, Mendel University, Brno, Czech Republic

Correspondence: Jan Vondráek, Institute of Biophysics, Královopolská 135, 612 65 Brno, Czech Republic. E-mail: hivrisek{at}ibp.cz

Differentiating myeloid cells may become resistant to various apoptotic stimuli. In the present study, dimethyl sulfoxide (DMSO) and all-trans retinoic acid (ATRA) were found to modulate the sensitivity of HL-60 cells to death receptor-mediated apoptosis in a time-dependent manner. During the early stages of differentiation, DMSO treatment increased the response of HL-60 cells to tumor necrosis factor ; (TNF-), but enhanced responsiveness was lost during later differentiation stages. In contrast, ATRA treatment induced resistance to TNF--induced apoptosis. HL-60 cells were resistant to Fas-mediated apoptosis but were sensitized by culturing in serum-free conditions. Similar to its effect on TNF- sensitivity, DMSO pretreatment augmented the response to Fas-mediated signaling, which coincided with increased expression of Fas on DMSO-pretreated cells. However, during the later stages of DMSO-induced differentiation, sensitivity to anti-Fas antibody-induced apoptosis declined significantly, although Fas expression was still elevated. The reduced sensitivity to anti-Fas treatment partially correlated with increased Fas-associated phosphatase-1 mRNA expression. Thus, regardless of either Fas up-regulation or potentiation of TNF--mediated apoptosis during early DMSO-induced differentiation, a slow increase in resistance to apoptosis mediated through these death receptors occurs during DMSO-induced differentiation, which contrasts with the rapid induction of resistance following treatment with ATRA.

Key Words: all-trans retinoic acid • dimethyl sulfoxide • Fas/CD95/APO-1 • TNF- • Bcl-2 • FAP-1

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