Retinoids play an important role in the control of lymphocyte function and homeostasis in the thymus. In this study, we show that the induction of growth arrest and apoptosis in a variety of
T-cell lymphoma cell lines, including Jurkat and Molt-4 cells, is highly specific for the synthetic
retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-
naphthalene carboxylic acid (
AHPN) since
all-trans retinoic acid (RA), the RAR-selective
retinoid TTAB, the RXR-selective
retinoid SR11217 and the
retinoid SR11302 exhibiting selective anti-AP1 activity, do not induce apoptosis or cause growth arrest. These findings support the concept that the effects of
AHPN on proliferation and induction of apoptosis are mediated by a novel signaling pathway.
AHPN-induced apoptosis is associated with an induction of internucleosomal DNA-fragmentation, increased
annexin V binding and a 30-fold stimulation of caspase-3-like activity. Overexpression of Bcl-2 in Molt-4 cells greatly inhibits the induction of apoptosis by
AHPN as indicated by the inhibition of DNA-fragmentation,
annexin V binding and caspase-3-like activity. However, Bcl-2 overexpression does not interfere with the ability of
AHPN to cause growth arrest or accumulation of cells in the early S-phase of the cell cycle, indicating that the effects of
AHPN on growth arrest can be uncoupled from the effects on apoptosis. The
caspase inhibitor
Z-VAD-FMK, at concentrations that totally block
caspase activity, delays but does not prevent cell death and does not affect the accumulation of cells in the S-phase of the cell cycle. Our results show that induction of caspase-3-like activity plays an important role in the execution of
AHPN-induced apoptosis but cells can undergo cell death in the absence of this activity suggesting that
AHPN-induced cell death involves
caspase-dependent and -independent mechanisms.