Small Molecule Inhibition of the Steroid Receptor Coactivators, SRC-3 and SRC-1
Small Molecule Inhibition of the Steroid Receptor Coactivators, SRC-3 and SRC-1
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DOI：
10.1210/me.2011-1222
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发表时间：
2011-12-01
影响因子：
--
通讯作者：
O'Malley, Bert W.
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文献类型：
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作者：
Wang, Ying;Lonard, David M.;O'Malley, Bert W.
类固醇受体共激活因子(SRC)-1和SRC-3的过表达与癌症的发生、转移、晚期疾病和化疗耐药有关。在大多数情况下，SRC-1和SRC-3已被证明通过激活核受体和多种生长因子信号级联来促进肿瘤细胞生长，从而导致肿瘤细胞生长不受控制。到目前为止，大多数靶向化疗药物在很大程度上被设计为一次阻断一条途径，但癌症经常通过切换到其他生长因子途径来获得耐药性。我们认为，针对SRC共激活因子的化疗药物的开发应该是特别有效的治疗方法，SRC共激活因子位于多个细胞生长信号网络和转录因子的联系上。为了证实这一假设，我们报道了2,2'-双-(甲酰基-1,6,7-三羟基-5-异丙基-3-甲基萘（棉酚）作为助活化剂SRC-1和SRC-3的小分子抑制剂的发现。我们的数据表明，棉酚在其受体相互作用域直接与SRC-3结合。在MCF-7乳腺癌细胞中，棉酚选择性地降低了SRC-1和SRC-3的细胞蛋白浓度，而不会改变整体蛋白表达模式、SRC-2或其他辅助激活因子，如p300和辅助激活因子相关的精氨酸甲基转移酶1。棉酚可降低前列腺癌、肺癌和肝癌细胞系中SRC-3的浓度。棉酚在促进SRC-3下调的相同癌细胞系中抑制细胞活力。此外，棉酚使肺癌和乳腺癌细胞系对其他化疗药物的抑制作用增敏。重要的是，棉酚对癌细胞有选择性的细胞毒性，而正常细胞的活力不受影响。这些数据建立了原理证明，SRC-1和SRC-3共激活剂作为一类药物是可获得的化疗靶点。鉴于SRC-1/SRC-3小分子抑制剂作为多种细胞生长信号系统的整合者的功能，它们构成了一类新的药物，有潜力成为能够击败获得性癌细胞耐药机制方面的新型化疗药物。（分子内分泌学25:2041-2053,2011）
Overexpression of steroid receptor coactivator (SRC)-1 and SRC-3 is associated with cancer initiation, metastasis, advanced disease, and resistance to chemotherapy. In most of these cases, SRC-1 and SRC-3 have been shown to promote tumor cell growth by activating nuclear receptor and multiple growth factor signaling cascades that lead to uncontrolled tumor cell growth. Up until now, most targeted chemotherapeutic drugs have been designed largely to block a single pathway at a time, but cancers frequently acquire resistance by switching to alternative growth factor pathways. We reason that the development of chemotherapeutic agents against SRC coactivators that sit at the nexus of multiple cell growth signaling networks and transcriptional factors should be particularly effective therapeutics. To substantiate this hypothesis, we report the discovery of 2,2'-bis-(Formyl-1,6,7-trihydroxy-5-isopropyl-3-methylnaphthalene (gossypol) as a small molecule inhibitor of coactivator SRC-1 and SRC-3. Our data indicate that gossypol binds directly to SRC-3 in its receptor interacting domain. In MCF-7 breast cancer cells, gossypol selectively reduces the cellular protein concentrations of SRC-1 and SRC-3 without generally altering overall protein expression patterns, SRC-2, or other coactivators, such as p300 and coactivator-associated arginine methyltransferase 1. Gossypol reduces the concentration of SRC-3 in prostate, lung, and liver cancer cell lines. Gossypol inhibits cell viability in the same cancer cell lines where it promotes SRC-3 down-regulation. Additionally, gossypol sensitizes lung and breast cancer cell lines to the inhibitory effects of other chemotherapeutic agents. Importantly, gossypol is selectively cytotoxic to cancer cells, whereas normal cell viability is not affected. This data establish the proof-of-principle that, as a class, SRC-1 and SRC-3 coactivators are accessible chemotherapeutic targets. Given their function as integrators of multiple cell growth signaling systems, SRC-1/SRC-3 small molecule inhibitors comprise a new class of drugs that have potential as novel chemotherapeutics able to defeat aspects of acquired cancer cell resistance mechanisms. (Molecular Endocrinology 25:2041-2053, 2011)