Blocking activator protein-1 activity, but not activating retinoic acid response element, is required for the antitumor promotion effect of retinoic acid
Blocking activator protein-1 activity, but not activating retinoic acid response element, is required for the antitumor promotion effect of retinoic acid
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DOI：
10.1073/pnas.94.11.5826
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发表时间：
1997-05-27
影响因子：
11.1
通讯作者：
Dong, ZG
中科院分区：
文献类型：
--
作者：
Huang, CS;Ma, WY;Dong, ZG
维甲酸是最有前景的化疗和化学预防癌症药物之一，其抗肿瘤活性可能与阻断激活蛋白-1(ap-1)活性或激活维甲酸反应元件(Rare)有关。然而，体内研究缺乏这一假说的证据。为了解决这一问题，我们使用了AP-1-荧光素酶转基因小鼠作为致癌模型，新合成的维甲酸既是AP-1激活的选择性抑制剂，又是稀有的选择性激活剂。结果表明，SR11302是AP-1抑制特异性的维甲酸，以及其他AP-1抑制剂如反式维甲酸和氟康酮丙酮等。显著抑制12-O-十四烷基佛波酯-13-乙酸酯诱导的小鼠皮肤乳头状瘤的形成和AP-1的激活(P<；相反，反复应用具有罕见反式激活活性但没有AP-1抑制作用的维甲酸SR11235并没有显著抑制乳头状瘤的形成和AP-1的激活(P>；0.05)，这些结果首次提供了体内证据，表明维甲酸的抗肿瘤作用是通过阻断AP-1的活性来实现的，而不是通过激活稀有的。
Retinoic acid is one of the most promising drugs for chemotherapy and chemoprevention of cancer, Either blocking activator protein-1 (AP-1) activity or activating retinoic acid response element (RARE) have been proposed to be responsible for its antitumor activity, However, evidence for this hypothesis is lacking in vivo studies, To address this issue, we used an AP-1-luciferase transgenic mouse as a carcinogenesis model and new synthetic retinoids that are either selective inhibitors of AP-1 activation or selective activators of the RARE, The results showed that the SR11302, an AP-1 inhibition-specific retinoid, and other AP-1 inhibitors such as trans-retinoic acid and fluocinolone acetonide, markedly inhibit both 12-O-tetradecanoylphorbol-13-acetate-induced papilloma formation and AP-1 activation in 7,12-dimethyl benz(a)anthracene-initiated mouse skin (P < 0.05), In contrast, repeated applications of SR11235 a retinoid with RARE transactivating activity, but devoid of AP-1 inhibiting effect, did not cause significant inhibition of papilloma formation and AP-1 activation (P > 0.05), These results provide the first in vivo evidence that the antitumor effect of retinoids is mediated by blocking AP-1 activity, but not by activation of RARE.