Modulation of retinoic acid receptor function alters the growth inhibitory response of oral SCC cells to retinoids
Modulation of retinoic acid receptor function alters the growth inhibitory response of oral SCC cells to retinoids
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DOI：
10.1038/sj.onc.1203436
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发表时间：
2000-03-09
期刊：
影响因子：
8
通讯作者：
Soprano, KJ
中科院分区：
文献类型：
--
作者：
Le, Q;Dawson, MI;Soprano, KJ
类维甲酸已被证明可以抑制包括乳腺癌、卵巢癌和鳞状细胞癌（SCC）在内的许多人类肿瘤细胞的生长，虽然类维甲酸介导的生长抑制的确切机制尚不清楚，但维甲酸受体（RARs）和类维甲酸X受体（RXRs）的作用已在乳腺癌和卵巢肿瘤细胞模型中得到证实。我们开始确定RAR/RXR功能的调节是否会改变口腔SCC细胞的类视黄醇敏感性。我们发现，SCC细胞的生长被全反式维甲酸（trans-RA）或合成的构象限制性RAR γ选择性维甲酸MM11254和MM11389显著抑制。为了证明RAR/RXR功能在这一过程中的作用，制备了稳定的口腔SCC细胞克隆，组成性地过表达显性负突变体RAR β 2 (R269Q)，并显示出RAR/RXR转录活化活性降低。我们发现RAR/RXR功能降低的口腔SCC细胞对all-trans-RA、MM11254和MM11389的生长抑制产生抗性。同样，用RAR γ拮抗剂MM11253治疗口服SCC细胞被发现阻断MM11254和MM11389抑制SCC细胞生长的能力。因此，通过使用RAR- γ选择性激动剂、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SCC细胞对类维生素a的生长抑制反应。
Retinoids have been shown to inhibit the growth of many human tumor cells including breast, ovarian and squamous cell carcinoma (SCC), While the exact mechanism of retinoid mediated growth suppression is not known, a role for the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has been established in both the breast and ovarian tumor cell models. We set out to determine if modulation of RAR/RXR function would alter the retinoid sensitivity of oral SCC cells. We found that the growth of SCC cells was significantly inhibited by treatment with either all-trans-retinoic acid (trans-RA) or the synthetic, conformationally restricted RAR gamma selective retinoids MM11254 and MM11389. In order to demonstrate a role for RAR/RXR function in this process, stable oral SCC cell clones constitutively overexpressing the dominant negative mutant RAR beta 2 (R269Q) were prepared and shown to exhibit reduced RAR/RXR transcriptional transactivation activity. We found that oral SCC cells exhibiting reduced RAR/RXR function became resistant to growth inhibition by all-trans-RA, MM11254 and MM11389. Likewise, treatment of oral SCC cells with the RAR gamma antagonist MM11253 was found to block the ability of MM11254 and MM11389 to inhibit SCC cell growth. Thus, modulation of RAR function through the use of RAR-gamma selective agonists, an RAR-gamma selective antagonist or a pan-RAR dominant negative mutant significantly alters the growth inhibitory response of oral SCC cells to retinoids.