Retinoic acid receptors and cancer
Retinoic acid receptors and cancer
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DOI：
10.1093/jn/132.12.3809s
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发表时间：
2002-12-01
影响因子：
4.2
通讯作者：
Soprano, DR
中科院分区：
文献类型：
--
作者：
Soprano, KJ;Soprano, DR
类维生素a已被证明能抑制许多人类肿瘤细胞的生长。尽管类维甲酸介导的生长抑制的确切分子机制尚不清楚，但维甲酸受体（RARs）和类维甲酸X受体（RXRs）的重要性已在建立的许多肿瘤细胞模型中得到证实。我们想确定RAR/RXR功能的调节是否会改变口腔鳞癌细胞（SCCs）的类视黄醇敏感性。全反式维甲酸（RA）或合成的构象限制性rar - γ选择性维甲酸SR 11254和SR 11389均能显著抑制SCCs的生长。相比之下，组成性过表达小鼠显性负突变体RAR- β (R269Q)的稳定口腔SCC克隆显示出RAR/RXR转录激活功能降低，并且对RA、SR 11254和SR 11389的生长抑制敏感性降低。同样，rar - γ拮抗剂SR 11253被发现可以阻断SR 11254和SR 11389抑制SCC生长的能力。这些结果表明，通过使用RAR- γ选择性拮抗剂或泛RAR显性阴性突变体来调节RAR功能，可显著改变口服SCCs对类维生素a的生长抑制反应。
Retinoids have been shown to inhibit the growth of many human tumor cells. Although the exact molecular mechanism of retinoid-mediated growth suppression remains known, the importance of the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has been in established a number of tumor cell models. We wanted to determine if modulation of RAR/RXR function would alter the retinoid sensitivity of oral squamous carcinoma cells (SCCs). Growth of SCCs was significantly suppressed by treatment with either all-trans retinoic acid (RA) or the synthetic, conformationally restricted RAR-gamma-selective retinoids SR 11254 and SR 11389. In contrast, stable oral SCC clones that constitutively overexpressed the mouse dominant negative mutant, RAR-beta (R269Q), were shown to exhibit reduced RAR/RXR transcriptional transactivation function and reduced sensitivity to growth inhibition by RA, SR 11254 and SR 11389. Likewise, the RAR-gamma antagonist SR 11253 was found to block the ability of SR 11254 and SR 11389 to inhibit SCC growth. These results indicate that modulation of RAR function through the use of either an RAR-gamma-selective antagonist or a pan-RAR dominant negative mutant significantly alters the growth inhibitory response of oral SCCs to retinoids.