在本研究中，我们发现了与卵巢癌耐紫杉醇药物治疗相关的新机制——腺苷酸酯酶相互作用蛋白-1（NAC1）的核外转运。我们证明了BTB/POZ基因家族的核因子NAC1在氨基末端（aa 17-28）具有核外转运信号（NES），在肿瘤细胞接受多西他赛治疗时，该 NES 对于 NAC1 核-细胞浆穿梭至关重要。在机制上，核外转运的 NAC1 通过其 BTB 和 BOZ 结构域分别结合了 Cul3 和 Cyclin B1，并且细胞质中的 NAC1-Cul3 E3泛素连接酶复合物促进了 Cyclin B1 的泛素化和降解，从而促进有丝分裂的结束并导致细胞对于多西他赛的耐药。我们还在体外和体内实验中证明，TP-CH-1178，一种可渗透细胞膜的多肽针对 NAC1 NES 模体，可以阻止 NAC1 的核外转运，干扰 Cyclin B1 的降解并使卵巢癌细胞对多西他赛产生敏感性。本研究不仅揭示了 NAC1 核外转运受到调控以及与 NAC1-Cul3 复合物有关的 Cyclin B1 降解和有丝分裂的结束之间的新机制，同时也将 NAC1 核外转运途径作为卵巢癌和其他恶性肿瘤中调节紫杉醇耐药性的潜在靶点。Copyright © 2023 Elsevier Inc. All rights reserved.

In this study, we uncovered the nuclear export of nucleus accumbens-associated protein-1 (NAC1) as a novel mechanism involved in ovarian cancer resistance to taxanes, the chemotherapeutic drugs commonly used in treatment of this malignancy. We showed that NAC1, a nuclear factor of the BTB/POZ gene family, has a nuclear export signal (NES) at the N terminus (aa 17-28), and this NES critically contributes to the NAC1 nuclear-cytoplasmic shuttling when tumor cells were treated with docetaxel. Mechanistically, the nuclear-exported NAC1 bound to cullin3 (Cul3) and Cyclin B1 via its BTB and BOZ domains respectively, and the cyto-NAC1-Cul3 E3 ubiquitin ligase complex promotes the ubiquitination and degradation of Cyclin B1, thereby facilitating mitotic exit and leading to cellular resistance to docetaxel. We also showed in in vitro and in vivo experiments that TP-CH-1178, a membrane-permeable polypeptide against the NAC1 NES motif, blocked the nuclear export of NAC1, interfered with the degradation of Cyclin B1 and sensitized ovarian cancer cells to docetaxel. This study not only reveals a novel mechanism by which the NAC1 nuclear export is regulated and Cyclin B1 degradation and mitotic exit are impacted by the NAC1-Cul3 complex, but also provides the nuclear-export pathway of NAC1 as a potential target for modulating taxanes resistance in ovarian cancer and other malignancies.Copyright © 2023 Elsevier Inc. All rights reserved.