Holmes William F, Soprano Dianne Robert, Soprano Kenneth J
Department of Microbiology & Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
J Biol Chem. 2002 Nov 22;277(47):45408-19. doi: 10.1074/jbc.M204600200. Epub 2002 Sep 16.
Retinoids have great promise in the area of cancer therapy and chemoprevention. Although some tumor cells are sensitive to the growth inhibitory effect of all-trans-retinoic acid (ATRA), many ovarian tumor cells are not. 6-((1-Admantyl)-4-hydroxyphenyl)-2-naphthalenecarboxylic acid (CD437) is a conformationally restricted synthetic retinoid that induces growth arrest and apoptosis in both ATRA-sensitive and ATRA-resistant ovarian tumor cell lines. To better understand the mechanism by which CD437 induces apoptosis in ovarian tumor cell lines, we prepared a cell line, CA-CD437R, from the ATRA-sensitive ovarian cell line, CA-OV-3, which was resistant to CD437. We found that the CD437-resistant cell line was also resistant to the induction of apoptosis by tumor necrosis factor-alpha but not resistant to the induction of apoptosis by another synthetic retinoid, fenretinide N-(4-hydroxyphenyl)retinamide. We also show that this cell line remains ATRA-sensitive and exhibits no deficiencies in RAR function. Analysis of this CD437-resistant cell line suggests that the pathway for induction of apoptosis by CD437 is similar to the pathway utilized by tumor necrosis factor-alpha and different from the pathway induced by the synthetic retinoid, fenretinide N-(4-hydroxyphenyl)retinamide. The CA-CD437R cell line is a valuable tool, permitting us to further elucidate the molecular events that mediate apoptosis induced by CD437 and other synthetic retinoids. Results of experiments utilizing this cell line suggest that the alteration responsible for resistance of CA-CD437R cells to CD437 induced event maps after the activation of p38 and TR3 expression, prior to mitochondrial depolarization, subsequent release of cytochrome c and activation of caspase-9 and caspase-3.
维甲酸类药物在癌症治疗和化学预防领域具有巨大潜力。尽管一些肿瘤细胞对全反式维甲酸（ATRA）的生长抑制作用敏感，但许多卵巢肿瘤细胞并不敏感。6-((1-金刚烷基)-4-羟基苯基)-2-萘甲酸（CD437）是一种构象受限的合成维甲酸，可诱导ATRA敏感和ATRA耐药的卵巢肿瘤细胞系发生生长停滞和凋亡。为了更好地理解CD437诱导卵巢肿瘤细胞系凋亡的机制，我们从对CD437耐药的ATRA敏感卵巢细胞系CA-OV-3制备了一个细胞系CA-CD437R。我们发现，对CD437耐药的细胞系对肿瘤坏死因子-α诱导的凋亡也耐药，但对另一种合成维甲酸N-(4-羟基苯基)视黄酰胺诱导的凋亡不耐药。我们还表明，该细胞系对ATRA仍敏感，且RAR功能无缺陷。对这个对CD437耐药的细胞系的分析表明，CD437诱导凋亡的途径与肿瘤坏死因子-α利用的途径相似，与合成维甲酸N-(4-羟基苯基)视黄酰胺诱导的途径不同。CA-CD437R细胞系是一个有价值的工具，使我们能够进一步阐明介导CD437和其他合成维甲酸诱导凋亡的分子事件。利用该细胞系进行的实验结果表明，导致CA-CD437R细胞对CD437诱导事件耐药的改变发生在p38激活和TR3表达之后、线粒体去极化之前、随后细胞色素c释放以及caspase-9和caspase-3激活之前。
