Small molecule nAS-E targeting cAMP response element binding protein (CREB) and CREB-binding protein interaction inhibits breast cancer bone metastasis
Small molecule nAS-E targeting cAMP response element binding protein (CREB) and CREB-binding protein interaction inhibits breast cancer bone metastasis
复制标题
小分子nAS-E靶向cAMP反应元件结合蛋白（CREB）和CREB结合蛋白相互作用抑制乳腺癌骨转移
DOI：
10.1111/jcmm.14024
复制
发表时间：
2019-02-01
影响因子：
5.3
通讯作者：
Deng, Lianfu
中科院分区：
文献类型：
--
作者：
Jiang, Min;Yan, Yufei;Deng, Lianfu
骨是乳腺癌最常见的转移部位。骨转移病灶中破骨细胞的过度活动常引起骨质溶解。环腺苷酸（cAMP）反应元件结合蛋白（CREB）具有多种生物学功能，包括乳腺癌细胞的转化和永生化。此外，有证据表明CREB在破骨细胞生成和骨吸收中起关键作用。有机小分子具有良好的药代动力学特性和特异性，靶向CREB-CBP（CREB-binding protein，CREB-结合蛋白）相互作用，抑制CREB介导的基因转录，作为肿瘤治疗药物受到越来越多的关注。我们最近发现萘酚AS-E（nAS-E）是一种通过抑制CREB-CBP相互作用的CREB介导的基因转录的细胞渗透性抑制剂。在本研究中，我们首次在体外检测了nAS-E对乳腺癌细胞增殖、存活、迁移以及破骨细胞形成和骨吸收的影响。我们的研究结果表明，nAS-E抑制乳腺癌细胞的增殖，迁移，存活和抑制破骨细胞分化以及通过抑制CREB-CBP相互作用的骨吸收。此外，还评价了nAS-E在预防乳腺癌诱导的骨质溶解方面的体内作用。我们的结果表明，nAS-E可以逆转MDA-MB-231肿瘤诱导的骨丢失。这些结果表明，靶向CREB-CBP相互作用的小分子抑制CREB介导的基因转录可能是治疗乳腺癌骨转移的潜在方法。
Bone is the most common metastatic site for breast cancer. The excessive osteoclast activity in the metastatic bone lesions often produces osteolysis. The cyclic-AMP (cAMP)-response element binding protein (CREB) serves a variety of biological functions including the transformation and immortalization of breast cancer cells. In addition, evidence has shown that CREB plays a key role in osteoclastgenesis and bone resorption. Small organic molecules with good pharmacokinetic properties and specificity, targeting CREB-CBP (CREB-binding protein) interaction to inhibit CREB-mediated gene transcription have attracted more considerations as cancer therapeutics. We recently identified naphthol AS-E (nAS-E) as a cell-permeable inhibitor of CREB-mediated gene transcription through inhibiting CREB-CBP interaction. In this study, we tested the effect of nAS-E on breast cancer cell proliferation, survival, migration as well as osteoclast formation and bone resorption in vitro for the first time. Our results demonstrated that nAS-E inhibited breast cancer cell proliferation, migration, survival and suppressed osteoclast differentiation as well as bone resorption through inhibiting CREB-CBP interaction. In addition, the in vivo effect of nAS-E in protecting against breast cancer-induced osteolysis was evaluated. Our results indicated that nAS-E could reverse bone loss induced by MDA-MB-231 tumour. These results suggest that small molecules targeting CREB-CBP interaction to inhibit CREB-mediated gene transcription might be a potential approach for the treatment of breast cancer bone metastasis.