The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity.
The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity.
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DOI：
10.1016/j.redox.2022.102291
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发表时间：
2022-05
期刊：
影响因子：
11.4
通讯作者：
de la Vega L
中科院分区：
文献类型：
--
作者：
Casares L;Moreno R;Ali KX;Higgins M;Dayalan Naidu S;Neill G;Cassin L;Kiib AE;Svenningsen EB;Minassi A;Honda T;Poulsen TB;Wiel C;Sayin VI;Dinkova-Kostova AT;Olagnier D;de la Vega L
转录因子 BACH1 是多种与氧化应激和炎症以及癌症转移相关的慢性疾病的潜在治疗靶点。然而，仅描述了少数 BACH1 降解剂/抑制剂。 BACH1 是血红素加氧酶 1 (HMOX1) 的转录抑制因子，受转录因子 NRF2 正向调节，并且可被合成齐墩果烷三萜类化合物 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic Acid (CDDO) 的衍生物高度诱导。这些化合物的大部分治疗活性归因于它们的抗炎和抗氧化特性，这些特性被广泛归因于它们激活 NRF2 的能力。然而，由于作用范围如此广泛，这些化合物还有其他尚未完全确定的分子靶点，并且对其治疗特性也可能很重要。在此，我们将 BACH1 确定为两种 CDDO 衍生物（CDDO-Me 和 CDDO-TFEA）的靶点，但不是 CDDO 的靶点。虽然 CDDO 和 CDDO 衍生物都类似地激活 NRF2，但只有 CDDO-Me 和 CDDO-TFEA 抑制 BACH1，这解释了与未修饰的 CDDO 相比，这些 CDDO 衍生物作为 HMOX1 诱导剂的效力要高得多。值得注意的是，我们证明 CDDO-Me 和 CDDO-TFEA 通过一种新机制抑制 BACH1，该机制降低 BACH1 核水平，同时积累其细胞质形式。在体外模型中，两种 CDDO 衍生物均以 BACH1 依赖性和 NRF2 独立的方式损害肺癌细胞侵袭，而 CDDO 则无活性。总而言之，我们的研究将 CDDO-Me 和 CDDO-TFEA 确定为双重 KEAP1/BACH1 抑制剂，为这些药物的进一步治疗用途提供了理论依据。
The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these compounds have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of two CDDO-derivatives (CDDO-Me and CDDO-TFEA), but not of CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-Me and CDDO-TFEA inhibit BACH1, which explains the much higher potency of these CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-Me and CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both CDDO-derivatives impaired lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while CDDO was inactive. Altogether, our study identifies CDDO-Me and CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.
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DOI：
10.1016/j.biopha.2016.09.021
发表时间：
2016-12-01
期刊：
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
影响因子：
--
作者：
Davudian, Sadaf;Shajari, Neda;Baradaran, Behzad
通讯作者：
Baradaran, Behzad
影响因子：
64.5
作者：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
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影响因子：
11.2
作者：
Liby, Karen;Royce, Darlene B.;Sporn, Michael B.
通讯作者：
Sporn, Michael B.
DOI：
10.1073/pnas.0500815102
发表时间：
2005-03-22
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Liby, KT;Talalay, P
通讯作者：
Talalay, P