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Correction: The possible involvement of circRNA DMNT1/p53/JAK/STAT in gestational diabetes mellitus and preeclampsia. 更正:circRNA DMNT1/p53/JAK/STAT 可能与妊娠糖尿病和子痫前期有关。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 DOI: 10.1038/s41420-024-02065-5
Dongqin Bao, Chaohui Zhuang, Yan Jiao, Li Yang
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引用次数: 0
Overexpressed nicotinamide N‑methyltransferase in endometrial stromal cells induced by macrophages and estradiol contributes to cell proliferation in endometriosis. 在巨噬细胞和雌二醇的诱导下,子宫内膜基质细胞中烟酰胺 N-甲基转移酶过度表达,导致子宫内膜异位症细胞增殖。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-03 DOI: 10.1038/s41420-024-02229-3
Shuhui Hou, Hui Xu, Shating Lei, Dong Zhao

Endometriosis, an estrogen-dependent chronic inflammatory condition, afflicts reproductive-aged women. However, the underlying pathological mechanisms remain to be elucidated. Nicotinamide N-methyltransferase (NNMT) is a critical enzyme involved in cellular metabolism and methylation regulation. This study investigated the role of NNMT in endometriosis. By analyzing datasets GSE5108, GSE7305, GSE141549, GSE23339, and GSE25628, we identified a significant overexpression of NNMT in the eutopic endometrium and ectopic lesions of endometriosis patients compared to normal endometrium. Furthermore, NNMT was upregulated in collected endometrioma specimens and isolated primary endometrial stromal cells (ESCs) compared to their respective controls. Inhibition of NNMT using JBSNF-000088 attenuated the proliferation, migration, and invasion of ESCs. In vivo, treatment of mouse models of endometriosis with JBSNF-000088 resulted in a marked reduction in lesion weight and quantity. NNMT expression in ESCs was dose-dependently upregulated by 17β-estradiol at concentrations of 1 nM, 10 nM, and 100 nM, an effect that was attenuated by 10 nM progesterone. Additionally, treating HESCs with macrophage-conditioned medium elevated NNMT expression at both mRNA and protein levels. Knockdown of NNMT impeded the proliferation, migration, and invasion of ESCs, which was paralleled by decreased phosphorylation levels of Erb-b2 receptor tyrosine kinase 4 (ERBB4), PI3K, and AKT. Conversely, overexpressing ERBB4 mitigated the NNMT knockdown-induced decline in phosphorylated PI3K and AKT and rescued the proliferation of ESCs. Altogether, these results indicate that the overexpression of NNMT induced by estrogen and macrophage interaction modulates ESC proliferation via the NNMT-ERBB4-PI3K/AKT signaling pathway, as well as promotes cellular migration and invasion, contributing to the development of endometriosis.

子宫内膜异位症是一种依赖雌激素的慢性炎症,困扰着育龄妇女。然而,其潜在的病理机制仍有待阐明。烟酰胺 N-甲基转移酶(NNMT)是一种参与细胞代谢和甲基化调节的关键酶。本研究调查了 NNMT 在子宫内膜异位症中的作用。通过分析数据集 GSE5108、GSE7305、GSE141549、GSE23339 和 GSE25628,我们发现与正常子宫内膜相比,NNMT 在子宫内膜异位症患者的异位内膜和异位病灶中显著过表达。此外,与各自的对照组相比,NNMT在收集的子宫内膜异位症标本和分离的原代子宫内膜基质细胞(ESC)中上调。使用 JBSNF-000088 抑制 NNMT 可减轻 ESCs 的增殖、迁移和侵袭。在体内,用 JBSNF-000088 治疗子宫内膜异位症小鼠模型可明显减轻病变的重量和数量。在 1 nM、10 nM 和 100 nM 的浓度下,17β-雌二醇会剂量依赖性地上调 ESC 中 NNMT 的表达,而 10 nM 的黄体酮会减弱这种效应。此外,用巨噬细胞条件培养基处理 HESCs 会在 mRNA 和蛋白质水平上提高 NNMT 的表达。敲除 NNMT 会阻碍 ESC 的增殖、迁移和侵袭,与此同时,Erb-b2 受体酪氨酸激酶 4(ERBB4)、PI3K 和 AKT 的磷酸化水平也会降低。相反,过表达 ERBB4 可减轻 NNMT 敲除诱导的磷酸化 PI3K 和 AKT 的下降,并挽救 ESCs 的增殖。总之,这些结果表明,雌激素和巨噬细胞相互作用诱导的NNMT过表达会通过NNMT-ERBB4-PI3K/AKT信号通路调节ESC增殖,并促进细胞迁移和侵袭,从而导致子宫内膜异位症的发生。
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引用次数: 0
Targeting the HECTD3-p62 axis increases the radiosensitivity of triple negative breast cancer cells. 靶向 HECTD3-p62 轴可提高三阴性乳腺癌细胞的放射敏感性。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-01 DOI: 10.1038/s41420-024-02154-5
Maobo Huang, Wenjing Liu, Zhuo Cheng, Fubing Li, Yanjie Kong, Chuanyu Yang, Yu Tang, Dewei Jiang, Wenhui Li, Yudie Hu, Jinhui Hu, PemaTenzin Puno, Ceshi Chen

Triple negative breast cancer is the most malignant subtype of breast cancer and current treatment options are limited. Radiotherapy is one of the primary therapeutic options for patients with TNBC. In this study, we discovered that the E3 ubiquitin ligase, HECTD3, promoted TNBC cell survival after irradiation. HECTD3 collaborated with UbcH5b to promote p62 ubiquitination and autophagy while HECTD3 deletion led to p62 accumulation in the nucleus in response to irradiation, thus inhibiting RNF168 mediated DNA damage repair. Furthermore, the HECTD3/UbcH5b inhibitor, PC3-15, increased the radiosensitivity of TNBC cells by inhibiting DNA damage repair. Taken together, we conclude that HECTD3 promotes autophagy and DNA damage repair in response to irradiation in a p62-denpendent manner, and that inhibition of the HECTD3-p62 axis could be a potential therapeutic strategy for patients with TNBC in addition to radiotherapy.

三阴性乳腺癌是恶性程度最高的乳腺癌亚型,目前的治疗方案有限。放疗是 TNBC 患者的主要治疗选择之一。在这项研究中,我们发现E3泛素连接酶HECTD3能促进TNBC细胞在照射后存活。HECTD3与UbcH5b合作促进p62泛素化和自噬,而HECTD3缺失会导致p62在辐照后在细胞核中积累,从而抑制RNF168介导的DNA损伤修复。此外,HECTD3/UbcH5b抑制剂PC3-15通过抑制DNA损伤修复增加了TNBC细胞的辐射敏感性。综上所述,我们得出结论:HECTD3以p62依赖的方式促进自噬和DNA损伤修复以应对辐照,抑制HECTD3-p62轴可能是TNBC患者放疗之外的一种潜在治疗策略。
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引用次数: 0
Lipids associated with autophagy: mechanisms and therapeutic targets. 与自噬有关的脂质:机制和治疗目标。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-30 DOI: 10.1038/s41420-024-02224-8
Michał Jarocki, Kacper Turek, Jolanta Saczko, Mounir Tarek, Julita Kulbacka

Autophagy is a molecular process essential for maintaining cellular homeostasis, with its impairment or dysregulation linked to the progression of various diseases in mammals. Specific lipids, including phosphoinositides, sphingolipids, and oxysterols, play pivotal roles in inducing and regulating autophagy, highlighting their significance in this intricate process. This review focuses on the critical involvement of these lipids in autophagy and lipophagy, providing a comprehensive overview of the current understanding of their functions. Moreover, we delve into how abnormalities in autophagy, influenced by these lipids, contribute to the pathogenesis of various diseases. These include age-related conditions such as cardiovascular diseases, neurodegenerative disorders, type 2 diabetes, and certain cancers, as well as inflammatory and liver diseases, skeletal muscle pathologies and age-related macular degeneration (AMD). This review aims to highlight function of lipids and their potential as therapeutic targets in treating diverse human pathologies by elucidating the specific roles of phosphoinositides, sphingolipids, and oxysterols in autophagy.

自噬是维持细胞稳态必不可少的分子过程,其损伤或失调与哺乳动物各种疾病的进展有关。特定的脂质,包括磷脂、鞘脂和氧基固醇,在诱导和调节自噬过程中发挥着关键作用,凸显了它们在这一复杂过程中的重要意义。本综述重点探讨了这些脂质在自噬和噬脂中的关键作用,全面概述了目前对其功能的理解。此外,我们还深入探讨了受这些脂质影响的自噬异常是如何导致各种疾病发病的。这些疾病包括与年龄有关的疾病,如心血管疾病、神经退行性疾病、2 型糖尿病和某些癌症,以及炎症和肝脏疾病、骨骼肌病变和老年性黄斑变性(AMD)。本综述旨在通过阐明磷脂、鞘磷脂和氧杂环醇在自噬中的特定作用,强调脂质的功能及其作为治疗靶点治疗各种人类病症的潜力。
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引用次数: 0
Myocardial ischemia-reperfusion injury upregulates nucleostemin expression via HIF-1α and c-Jun pathways and alleviates apoptosis by promoting autophagy. 心肌缺血再灌注损伤可通过 HIF-1α 和 c-Jun 通路上调 nucleostemin 的表达,并通过促进自噬缓解细胞凋亡。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-30 DOI: 10.1038/s41420-024-02221-x
Xiao Han, Zhicheng Jiang, Yufeng Hou, Xiaorong Zhou, Baoying Hu

Myocardial ischemia-reperfusion (I/R) injury, often arising from interventional therapy for acute myocardial infarction, leads to irreversible myocardial cell death. While previous studies indicate that nucleostemin (NS) is induced by myocardial I/R injury and mitigates myocardial cell apoptosis, the underlying mechanisms are poorly understood. Here, our study reveals that NS upregulation is critical for preventing cardiomyocyte death following myocardial I/R injury. Elevated NS protein levels were observed in myocardial I/R injury mouse and rat models, as well as Hypoxia/reoxygenation (H/R) cardiac cell lines (H9C2 cells). We identified binding sites for c-Jun and HIF-1α in the NS promoter region. Inhibition of JNK and HIF-1α led to a significant decrease in NS transcription and protein expression. Furthermore, inhibition of autophagy and NS expression promoted myocardial cell apoptosis in H/R. Notably, the cell model showed reduced LC3I transformation to LC3II, downregulated Beclin1, upregulated p62, and altered expression of autophagy-related proteins upon NS interference in H/R cells. These findings suggest that NS expression, driven by c-Jun and HIF-1α pathways, facilitates autophagy, providing protection against both myocardial I/R injury and H/R-induced cardiomyocyte apoptosis.

心肌缺血再灌注(I/R)损伤通常产生于急性心肌梗死的介入治疗,会导致心肌细胞不可逆转的死亡。以往的研究表明,心肌缺血再灌注损伤可诱导核固缩蛋白(NS)并减轻心肌细胞凋亡,但对其潜在机制却知之甚少。在此,我们的研究揭示了 NS 的上调对于防止心肌细胞在心肌 I/R 损伤后死亡至关重要。在心肌I/R损伤小鼠和大鼠模型以及缺氧/再氧合(H/R)心脏细胞系(H9C2细胞)中都观察到了NS蛋白水平的升高。我们在 NS 启动子区域发现了 c-Jun 和 HIF-1α 的结合位点。抑制 JNK 和 HIF-1α 可显著降低 NS 的转录和蛋白表达。此外,抑制自噬和NS表达可促进H/R中心肌细胞的凋亡。值得注意的是,H/R 细胞中的 NS 干扰后,细胞模型显示 LC3I 向 LC3II 转化减少,Beclin1 下调,p62 上调,自噬相关蛋白表达改变。这些研究结果表明,NS的表达在c-Jun和HIF-1α通路的驱动下促进了自噬,为防止心肌I/R损伤和H/R诱导的心肌细胞凋亡提供了保护。
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引用次数: 0
Mitophagy: insights into its signaling molecules, biological functions, and therapeutic potential in breast cancer. 有丝分裂:对其信号分子、生物功能和乳腺癌治疗潜力的深入研究。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-29 DOI: 10.1038/s41420-024-02226-6
Cong Chen, Aizhai Xiang, Xia Lin, Jufeng Guo, Jian Liu, Shufang Hu, Tao Rui, Qianwei Ye

Mitophagy, a form of selective autophagy that removes damaged or dysfunctional mitochondria, plays a crucial role in maintaining mitochondrial and cellular homeostasis. Recent findings suggest that defective mitophagy is closely associated with various diseases, including breast cancer. Moreover, a better understanding of the multifaceted roles of mitophagy in breast cancer progression is crucial for the treatment of this disease. Here, we will summarize the molecular mechanisms of mitophagy process. In addition, we highlight the expression patterns and roles of mitophagy-related signaling molecules in breast cancer progression and the potential implications of mitophagy for the development of breast cancer, aiming to provide better therapeutic strategies for breast cancer treatment.

有丝分裂是一种选择性自噬,可清除受损或功能障碍的线粒体,在维持线粒体和细胞平衡方面发挥着至关重要的作用。最新研究结果表明,有丝分裂缺陷与包括乳腺癌在内的多种疾病密切相关。此外,更好地了解有丝分裂在乳腺癌进展过程中的多方面作用对于该疾病的治疗至关重要。在此,我们将总结有丝分裂过程的分子机制。此外,我们还将强调有丝分裂相关信号分子在乳腺癌进展过程中的表达模式和作用,以及有丝分裂对乳腺癌发展的潜在影响,旨在为乳腺癌治疗提供更好的治疗策略。
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引用次数: 0
Nr1d1 inhibition mitigates intermittent hypoxia-induced pulmonary hypertension via Dusp1-mediated Erk1/2 deactivation and mitochondrial fission attenuation. 抑制 Nr1d1 可通过 Dusp1 介导的 Erk1/2 失活和线粒体裂变衰减缓解间歇性缺氧诱发的肺动脉高压。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-29 DOI: 10.1038/s41420-024-02219-5
Zhou Pan, Yan Yao, Xu Liu, Yixuan Wang, Xinyue Zhang, Shiqian Zha, Ke Hu

Intermittent hypoxia (IH) precipitates pulmonary vasoconstriction, culminating in the onset of pulmonary hypertension (PH) among individuals afflicted with sleep apnea. While Nuclear receptor subfamily 1 group D member 1 (Nr1d1) is progressively recognized as pivotal regulator of cellular physiology, the role in the pathogenesis of IH-induced PH remains largely uncharted. The expression of Nr1d1 was examined in IH-induced rodent PH and in IH-treated PASMCs. To elucidate the contribution of Nr1d1 to the development of IH-induced PH, we employed siRNA to modulate Nr1d1 expression in vitro and employed serotype 1 adeno-associated virus (AAV1) in vivo. Nr1d1 levels were elevated in IH-induced rodents PH lung tissues and IH-treated PASMCs. Knocking down Nr1d1 by AAV1 effectively inhibited PH progression in chronic IH-induced PH models. Mechanistic investigations identified dual specificity phosphatase 1 (Dusp1), as a direct target that Nr1d1 trans-repressed, mediating Nr1d1's regulatory influence on Erk1/2/Drp1 signaling. Nr1d1 deficiency ameliorates mitochondrial dysfunction and fission by restoring Dusp1 dysregulation and Drp1 phosphorylation. Activation of Erk1/2 with PMA reversed the Dusp1-mediated regulation of Drp1 phosphorylation, indicating the involvement of the Erk1/2 pathway in Drp1 phosphorylation controlled by Dusp1. Meanwhile, intermittent hypoxia induced more severe PH in Dusp1 knockout mice compared with wild-type mice. Our data unveil a novel role for Nr1d1 in IH-induced PH pathogenesis and an undisclosed Nr1d1-Dusp1 axis in PASMCs mitochondrial fission regulation.

间歇性缺氧(IH)会引起肺血管收缩,最终导致睡眠呼吸暂停患者出现肺动脉高压(PH)。虽然核受体 1 亚家族 D 组 1(Nr1d1)逐渐被认为是细胞生理的关键调节因子,但它在 IH 诱发的 PH 的发病机制中的作用在很大程度上仍是未知数。我们研究了 Nr1d1 在 IH 诱导的啮齿动物 PH 和 IH 处理的 PASMC 中的表达。为了阐明Nr1d1对IH诱导的PH发病的贡献,我们在体外使用siRNA调节Nr1d1的表达,在体内使用血清型1腺相关病毒(AAV1)。在 IH 诱导的啮齿动物 PH 肺组织和经 IH 处理的 PASMCs 中,Nr1d1 水平升高。通过AAV1敲除Nr1d1能有效抑制慢性IH诱导的PH模型的PH进展。机理研究发现,双重特异性磷酸酶1(Dusp1)是Nr1d1反式抑制的直接靶标,它介导了Nr1d1对Erk1/2/Drp1信号转导的调控作用。通过恢复 Dusp1 的失调和 Drp1 的磷酸化,Nr1d1 的缺乏可改善线粒体功能障碍和裂变。用PMA激活Erk1/2可逆转Dusp1介导的Drp1磷酸化调控,表明Erk1/2途径参与了Dusp1控制的Drp1磷酸化。同时,与野生型小鼠相比,间歇性缺氧会诱发Dusp1基因敲除小鼠更严重的PH。我们的数据揭示了 Nr1d1 在 IH 诱导的 PH 发病机制中的新作用,以及在 PASMC 线粒体裂变调控中尚未披露的 Nr1d1-Dusp1 轴。
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引用次数: 0
Unraveling the landscape of m6A RNA methylation in wound healing and scars. 揭开伤口愈合和疤痕中 m6A RNA 甲基化的面纱。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-29 DOI: 10.1038/s41420-024-02222-w
Qi Zhang, Liming Dong, Song Gong, Ting Wang

Wound healing is a complex process involving sequential stages of hemostasis, inflammation, proliferation, and remodeling. Multiple cell types and factors, including underlying conditions like diabetes and bacterial colonization, can influence healing outcomes and scar formation. N6-methyladenosine (m6A), a predominant RNA modification, plays crucial roles in gene expression regulation, impacting various biological processes and diseases. m6A regulates embryonic skin morphogenesis, wound repair, and pathophysiological processes like inflammation and angiogenesis. Recent studies have highlighted the role of m6A in wound healing, scar formation, and tissue remodeling. Additionally, m6A presents a unique expression pattern in pathological wounds and scars, potentially influencing wound healing and scar formation through modulating gene expression and cellular signaling, thereby serving as potential biomarkers or therapeutic targets. Targeting m6A modifications are potential strategies to enhance wound healing and reduce scar formation. This review aims to explore the roles and mechanisms of m6A RNA methylation in wound healing and scars, and discuss current challenges and perspectives. Continued research in this field will provide significant value for optimal wound repair and scar treatment.

伤口愈合是一个复杂的过程,涉及止血、炎症、增殖和重塑等连续阶段。多种细胞类型和因素,包括糖尿病和细菌定植等潜在条件,都会影响伤口愈合的结果和疤痕的形成。N6-甲基腺苷(m6A)是一种主要的 RNA 修饰物,在基因表达调控中起着至关重要的作用,影响着各种生物过程和疾病。最近的研究强调了 m6A 在伤口愈合、疤痕形成和组织重塑中的作用。此外,m6A 在病理伤口和疤痕中呈现出独特的表达模式,有可能通过调节基因表达和细胞信号传导影响伤口愈合和疤痕形成,从而成为潜在的生物标记物或治疗靶点。针对 m6A 修饰是促进伤口愈合和减少疤痕形成的潜在策略。本综述旨在探讨 m6A RNA 甲基化在伤口愈合和疤痕中的作用和机制,并讨论当前的挑战和前景。该领域的持续研究将为优化伤口修复和疤痕治疗提供重要价值。
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引用次数: 0
Quantitative chemical proteomics reveals that phenethyl isothiocyanate covalently targets BID to promote apoptosis. 定量化学蛋白质组学揭示了异硫氰酸苯乙酯可共价作用于 BID,从而促进细胞凋亡。
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-29 DOI: 10.1038/s41420-024-02225-7
Xiaoshu Dong, Xinqian Yu, Minghao Lu, Yaxin Xu, Liyan Zhou, Tao Peng

Naturally occurring isothiocyanates (ITCs) found in cruciferous vegetables, such as benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), and sulforaphane (SFN), have attracted significant research interest for their promising anti-cancer activity in vitro and in vivo. While the induction of apoptosis is recognized to play a key role in the anti-cancer effects of ITCs, the specific protein targets and associated upstream events underlying ITC-induced apoptosis remain unknown. In this study, we present a set of chemical probes that are derived from BITC, PEITC, and SFN and equipped with bioorthogonal alkynyl handles to systematically profile the target proteins of ITCs in live cancer cells. Using a competition-based quantitative chemical proteomics approach, we identify a range of candidate target proteins of ITCs enriched in biological processes such as apoptosis. We show that BID, an apoptosis regulator of the Bcl-2 family, is covalently modified by ITCs on its N-terminal cysteines. Functional characterization demonstrates that covalent binding to N-terminal cysteines of BID by PEITC results in conformational changes of the protein and disruption of the self-inhibitory interaction between N- and C-terminal regions of BID, thus unleashing the highly active C-terminal segment to exert downstream pro-apoptotic effects. Consistently, PEITC promotes the cleavage and mitochondrial translocation of BID, leading to a strong induction of apoptosis. We further show that mutation of N-terminal cysteines impairs the N- and C-terminal interaction of BID, relieving the self-inhibition and enhancing its apoptotic activity. Overall, our chemical proteomics profiling and functional studies not only reveal BID as the principal target of PEITC in mediating upstream events for the induction of apoptosis, but also uncover a novel molecular mechanism involving N-terminal cysteines within the first helix of BID in regulating its pro-apoptotic potential.

十字花科蔬菜中天然存在的异硫氰酸盐(ITCs),如异硫氰酸苄酯(BITC)、异硫氰酸苯乙酯(PEITC)和莱菔硫烷(SFN),因其在体外和体内具有良好的抗癌活性而引起了研究人员的极大兴趣。虽然诱导细胞凋亡被认为在 ITCs 的抗癌作用中起着关键作用,但 ITC 诱导细胞凋亡的特定蛋白靶点和相关上游事件仍不为人知。在本研究中,我们提出了一套从 BITC、PEITC 和 SFN 提取并配备生物正交炔柄的化学探针,用于系统分析活癌细胞中的 ITC 靶蛋白。利用基于竞争的定量化学蛋白质组学方法,我们确定了一系列富含凋亡等生物过程的 ITC 候选靶蛋白。我们发现 Bcl-2 家族的凋亡调节因子 BID 的 N 端半胱氨酸被 ITC 共价修饰。功能特性分析表明,PEITC 与 BID N 端半胱氨酸的共价结合会导致蛋白质构象的改变,并破坏 BID N 端和 C 端之间的自我抑制作用,从而释放高活性的 C 端片段,发挥下游的促凋亡效应。同样,PEITC 可促进 BID 的裂解和线粒体转运,从而强烈诱导细胞凋亡。我们进一步发现,N-端半胱氨酸的突变会损害 BID 的 N- 端和 C- 端相互作用,从而解除自我抑制并增强其凋亡活性。总之,我们的化学蛋白质组学分析和功能研究不仅揭示了 BID 是 PEITC 诱导细胞凋亡上游事件的主要靶点,而且还发现了一种新的分子机制,即 BID 第一螺旋内的 N 端半胱氨酸参与调控其促凋亡潜能。
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引用次数: 0
Xanthohumol overcomes osimertinib resistance via governing ubiquitination-modulated Ets-1 turnover. 黄腐醇通过调节泛素化调控的Ets-1周转克服奥希替尼耐药性
IF 6.1 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-28 DOI: 10.1038/s41420-024-02220-y
Ying Ma, Ruirui Wang, Jinzhuang Liao, Pengfei Guo, Qiang Wang, Wei Li

Non-small cell lung cancer (NSCLC) is a prevalent and fatal malignancy with a significant global impact. Recent advancements have introduced targeted therapies like tyrosine kinase inhibitors (TKIs) such as osimertinib, which have improved patient outcomes, particularly in those with EGFR mutations. Despite these advancements, acquired resistance to TKIs remains a significant challenge. Hence, one of the current research priorities is understanding the resistance mechanisms and identifying new therapeutic targets to improve therapeutic efficacy. Herein, we identified high expression of c-Met in osimertinib-resistant NSCLC cells, and depletion of c-Met significantly inhibited the proliferation of osimertinib-resistant cells and prolonged survival in mice, suggesting c-Met as an attractive therapeutic target. To identify effective anti-tumor agents targeting c-Met, we screened a compound library containing 641 natural products and found that only xanthohumol exhibited potent inhibitory effects against osimertinib-resistant NSCLC cells. Moreover, combination treatment with xanthohumol and osimertinib sensitized osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. Mechanistically, xanthohumol disrupted the interaction between USP9X and Ets-1, and inhibited the phosphorylation of Ets-1 at Thr38, promoting its degradation, thereby targeting the Ets-1/c-Met signaling axis and inducing intrinsic apoptosis in osimertinib-resistant NSCLC cells. Overall, the research highlights the critical role of targeting c-Met to address osimertinib resistance in NSCLC. By demonstrating the efficacy of xanthohumol in overcoming resistance and enhancing therapeutic outcomes, this study provides valuable insights and potential new strategies for improving the clinical management of NSCLC.

非小细胞肺癌(NSCLC)是一种常见的致命恶性肿瘤,对全球具有重大影响。最近的研究进展引入了酪氨酸激酶抑制剂(TKIs)等靶向疗法,如奥希替尼(osimertinib),这些疗法改善了患者的预后,尤其是表皮生长因子受体(EGFR)突变患者的预后。尽管取得了这些进展,TKIs 的获得性耐药性仍然是一项重大挑战。因此,目前的研究重点之一是了解耐药机制并确定新的治疗靶点以提高疗效。在本文中,我们发现c-Met在奥希替尼耐药的NSCLC细胞中高表达,消耗c-Met能显著抑制奥希替尼耐药细胞的增殖并延长小鼠的存活时间,这表明c-Met是一个有吸引力的治疗靶点。为了找到靶向c-Met的有效抗肿瘤药物,我们筛选了包含641种天然产物的化合物库,发现只有黄腐醇对奥希替尼耐药的NSCLC细胞具有强效抑制作用。此外,在体外和体内,黄腐醇和奥希替尼联合治疗可使奥希替尼耐药的NSCLC细胞对奥希替尼敏感。从机理上讲,黄腐醇破坏了USP9X和Ets-1之间的相互作用,抑制了Ets-1在Thr38处的磷酸化,促进其降解,从而靶向Ets-1/c-Met信号轴,诱导耐奥西美替尼的NSCLC细胞发生内在凋亡。总之,这项研究强调了靶向c-Met对解决NSCLC中奥西替尼耐药问题的关键作用。通过证明黄腐醇在克服耐药性和提高治疗效果方面的疗效,这项研究为改善NSCLC的临床治疗提供了宝贵的见解和潜在的新策略。
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Cell Death Discovery
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