Adachi H, Adams A, Hughes F M, Zhang J, Cidlowski J A, Jetten A M
Cell Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Cell Death Differ. 1998 Nov;5(11):973-83. doi: 10.1038/sj.cdd.4400445.
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.
维甲酸在胸腺中淋巴细胞功能的调控及内环境稳定方面发挥着重要作用。在本研究中，我们发现，包括Jurkat和Molt-4细胞在内的多种T细胞淋巴瘤细胞系中，生长停滞和凋亡的诱导对合成维甲酸6-[3-(1-金刚烷基)-4-羟基苯基]-2-萘甲酸（AHPN）具有高度特异性，因为全反式维甲酸（RA）、RAR选择性维甲酸TTAB、RXR选择性维甲酸SR11217以及具有选择性抗AP1活性的维甲酸SR11302均不诱导凋亡或导致生长停滞。这些发现支持了这样一种概念，即AHPN对增殖和凋亡诱导的作用是由一条新的信号通路介导的。AHPN诱导的凋亡与核小体间DNA片段化的诱导、膜联蛋白V结合增加以及caspase-3样活性的30倍刺激相关。Molt-4细胞中Bcl-2的过表达极大地抑制了AHPN诱导的凋亡，这通过DNA片段化、膜联蛋白V结合及caspase-3样活性的抑制得以表明。然而，Bcl-2过表达并不干扰AHPN导致生长停滞或使细胞在细胞周期早期S期积累的能力，这表明AHPN对生长停滞的作用可与对凋亡的作用相分离。caspase抑制剂Z-VAD-FMK在完全阻断caspase活性的浓度下，延迟但不阻止细胞死亡，且不影响细胞在细胞周期S期的积累。我们的结果表明，caspase-3样活性的诱导在AHPN诱导的凋亡执行中起重要作用，但细胞在缺乏这种活性的情况下仍可发生细胞死亡，这表明AHPN诱导的细胞死亡涉及caspase依赖性和非依赖性机制。
