更新于：2024-11-01

YAP1

更新于：2024-11-01

基本信息

别名

Protein yorkie homolog、Transcriptional coactivator YAP1、YAP

+ [6]

简介

Transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:17974916, PubMed:18280240, PubMed:18579750, PubMed:21364637, PubMed:30447097). The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288). Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation. Acts via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization (PubMed:25778702). Plays a key role in controlling cell proliferation in response to cell contact. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration (PubMed:18158288). The presence of TEAD transcription factors are required for it to stimulate gene expression, cell growth, anchorage-independent growth, and epithelial mesenchymal transition (EMT) induction (PubMed:18579750). Suppresses ciliogenesis via acting as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (PubMed:25849865). In conjunction with WWTR1, involved in the regulation of TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (By similarity). Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3). Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3).

关联

项与 YAP1 相关的药物

Verteporfin

维替泊芬

靶点

TEAD x YAP1

作用机制

TEAD 抑制剂 [+2]

在研机构

CHEPLAPHARM Arzneimittel GmbH [+2]

原研机构

Novartis Pharma AG

在研适应症

组织胞浆菌病 [+4]

非在研适应症

多发性基底细胞癌 [+1]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2000-04-12

Celastrol

雷公藤红素

靶点

CDC37 x COMMD3 x COMMD8 x HSP90 x LEPR x SHP2 x TEAD x YAP1

作用机制

CDC37拮抗剂 [+7]

在研机构

Osaka University [+5]

原研机构

The Ohio State University

在研适应症

骨折 [+4]

非在研适应症

糖尿病 [+2]

最高研发阶段临床2/3期

首次获批国家/地区-

首次获批日期1800-01-20

CBL-0137

靶点

FACT x NF-κB x YAP1 x p53

作用机制

FACT拮抗剂 [+3]

在研机构

Incuron LLC [+1]

原研机构

Cleveland BioLabs, Inc.

在研适应症

弥漫内生性脑桥神经胶质瘤 [+8]

非在研适应症

晚期恶性实体瘤 [+4]

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 YAP1 相关的临床试验

NCT06381154 / Not yet recruiting临床2期IIT

Photodynamic Priming to Facilitate Immunologic Activity of Anti-PD1 in Patients With Pancreatic Cancer

This phase II trial tests how well photoradiation with verteporfin and pembrolizumab plus standard of care chemotherapy works in treating patients with pancreatic cancer that cannot be removed by surgery (unresectable), that has spread to nearby tissue or lymph nodes (locally advanced) or to other places in the body (metastatic). Photoradiation uses light activated drugs, such as verteporfin, that become active when exposed to light. These activated drugs may kill tumor cells. Vertoporfin may also increase tumor response to immunotherapy. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX), work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Photoradiation with verteporfin and pembrolizumab plus standard of care chemotherapy may kill more tumor cells in patients with unresectable, locally advanced or metastatic pancreatic cancer.

开始日期2024-10-30

申办/合作机构

Mayo Clinic

[+1]

NCT06306638 / Recruiting临床1/2期IIT

A Phase I/II Study of Interstitial Photodynamic Therapy Following Palliative Radiotherapy for Patients With Inoperable Malignant Central Airway Obstruction

This phase I/II trial studies the side effects of interstitial photodynamic therapy following palliative radiotherapy and how well it works in treating patients with inoperable malignant central airway obstruction. Patients who have advanced stage cancer tumors in the lung can often have the breathing passages to the lung partially or completely blocked. These tumors could be due to lung cancer or other cancers (e.g., renal, breast, kidney, etc.) that spread to the lung. This blockage puts the patient at a higher risk for respiratory failure, post-obstructive pneumonia, and prolonged hospitalizations. Treatment for these patients may include bronchoscopic intervention (such as mechanical removal, stenting, laser cauterization, or ballooning), radiation therapy with and without chemotherapy. While palliative x-ray radiotherapy may help in shrinking the tumor, high dose curative radiotherapy that can ablate (a localized, nonsurgical destruction) the tumor also has high risk to cause significant toxicity, including bleeding, abnormal connections or passageways between organs or vessels and abnormal scar tissue that can also produce airway obstruction. Photodynamic therapy (PDT) is another possible treatment that can provide local control of the tumor. PDT consists of injecting a light sensitive drug (photosensitizer, PS) into the vein, waiting for the PS to accumulate in the tumor, and then activating it with a red laser light. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Giving interstitial photodynamic therapy following palliative radiotherapy may improve tumor response and survival without the serious side effects that are associated with the typical high dose curative x-ray radiotherapy alone in patients with malignant central airway obstruction.

开始日期2024-10-01

申办/合作机构

Roswell Park Comprehensive Cancer Center

IRCT20220424054643N2 / Recruiting临床2/3期IIT

Safety and Effect of Celastrol Supplementation on Rate of Union in Femur and Tibia Fracture Patients

开始日期2023-12-22

申办/合作机构

Shahid Beheshti University of Medical Sciences

100 项与 YAP1 相关的临床结果

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100 项与 YAP1 相关的转化医学

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0 项与 YAP1 相关的专利（医药）

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4,933

项与 YAP1 相关的文献（医药）

2025-03-01·Neural Regeneration Research

Salsolinol as an RNA m6A methylation inducer mediates dopaminergic neuronal death by regulating YAP1 and autophagy

Article

作者: Liu, Zongjian ; Chen, Xuechai ; Wang, Juan ; Wang, Jianan ; Zhang, Fangfang ; Ran, Yuanyuan ; Zhao, Tianyuan ; Li, Zihan

JOURNAL/nrgr/04.03/01300535-202503000-00032/figure1/v/2024-06-17T092413Z/r/image-tiff Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, Sal) is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an environmental toxin that causes Parkinson’s disease. However, the mechanism by which Sal mediates dopaminergic neuronal death remains unclear. In this study, we found that Sal significantly enhanced the global level of N6-methyladenosine (m6A) RNA methylation in PC12 cells, mainly by inducing the downregulation of the expression of m6A demethylases fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5). RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway. The m6A reader YTH domain-containing family protein 2 (YTHDF2) promoted the degradation of m6A-containing Yes-associated protein 1 (YAP1) mRNA, which is a downstream key effector in the Hippo signaling pathway. Additionally, downregulation of YAP1 promoted autophagy, indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity. These findings reveal the role of Sal on m6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy. Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson’s disease.

2025-02-01·Bioelectrochemistry

Low-energy electric shock ameliorates cell proliferation, morphallaxis, and regeneration via driving key regenerative proteins in earthworm and 3T3 cells

Article

作者: Selvan Christyraj, Johnson Retnaraj Samuel ; Balamurugan, Nivetha ; Vaidhyalingham, Ashwin Barath ; Nagaiah, Hari Prasath ; Rajagopalan, Kamarajan ; Selvan Christyraj, Jackson Durairaj ; Radhakrishnan, Periyasamy ; Dan, Vipin Mohan

Electric stimulation regulates many cellular processes like cell proliferation, differentiation, apoptosis and cellular migration. Despite its crucial role in regulating stem cells and regeneration, it remains underexplored in both in-vivo and in-vitro settings. In this study, Eudrilus eugeniae are subjected to electric stimulation (1.5 V) prior and after amputation and which augments regeneration up to double-time. Blocking epimorphosis using 2 M thymidine retracts regeneration kinetics to one-third but such inhibition was rescued by applying electric stimulation which propels an overactive morphallaxis pattern of regeneration. Excreting electric stimulation on control worms shows minimal impact, whereas it enhances the key regenerative proteins like VEGF, COX2, YAP, c-Myc, and Wnt3a on amputated worms. Upon blocking epimorphosis, all these key regenerative proteins are down-regulated but through electric stimulation, the cells are reprogrammed to express a triple fold of the mentioned regenerative proteins, that further promotes morphallaxis. In 3T3 cells, electric stimulation accelerates cell proliferation and migrations in 5 secs exposure and it exerts its function by overexpressing VEGF mediated by MEK1. Wnt3a expression was gradually upregulated in increasing exposure (5 and 25 secs) which aids in maintaining the stemness property. The molecular mechanism underlying regeneration capability can assist in designing novel therapeutic applications.

2025-01-01·Bone

Mechanotransduction pathways regulating YAP nuclear translocation under Yoda1 and vibration in osteocytes

Article

作者: Wang, Liyun ; Yokota, Hiroki ; You, Lidan ; Tang, Wentian ; Seaman, Kimberly ; Geng, Fei ; Song, Xin ; Bienenstock, Raphael ; Sassi, Amel ; Lin, Chun-Yu ; Sun, Yu ; Wu, Yuning

Yes-associated protein (YAP) is a mechanosensitive protein crucial for bone remodeling. Although research has identified pathways and components involved in YAP regulation, the precise mechanisms of its localization during Piezo1 activation or vibration remain unclear. Piezo1, a mechanosensitive ion channel, allows calcium ions to flow into cells upon activation. Recent studies suggest that combining Yoda1, a Piezo1 activator, with low-magnitude high-frequency (LMHF) vibration (>30 Hz, <1 g acceleration) enhances YAP nuclear translocation. This combination potentially improves the mechanoresponse and therapeutic efficacy of LMHF vibration in bone cells. This study aims to elucidate how Yoda1 and LMHF vibration regulate mechanosensitive structures and pathways, leading to YAP nuclear translocation in MLO-Y4 osteocyte like cells. We investigated the roles of the cytoskeleton and nuclear envelope (NE) in YAP activation under combined LMHF vibration and Yoda1 treatments. Additionally, we analyzed differentially expressed genes (DEGs) in MLO-Y4 cells subjected to these treatments and in Piezo1 knockdown MLO-Y4 cells exposed to vibration. Our findings indicated that increased YAP nuclear translocation with combined treatment may result from the distinct effects of Yoda1 and vibration. Specifically, Yoda1 influenced YAP through mechanisms involving actin and NE dynamics, while LMHF vibration may modulate YAP via the interleukin 6 (IL6)/signal transducer and activator of transcription 3 (STAT3) axis. This study provides new insights and potential therapeutic targets for osteocyte-related pathologies.

项与 YAP1 相关的新闻（医药）

2024-10-30

·生物制品圈

Cancer Cell前沿综述：癌症中的乳酸化

乳酸化是最近发现的一种蛋白质翻译后修饰，最初通过表观遗传机制与基因转录调控有关。然而，它在肿瘤发生中的作用（无论是作为主要驱动因素还是次要调节因子）仍不确定。今天，小编要和大家分享一篇2024年10月发表在Cancer Cell上的综述，文章总结了目前对乳酸化的理解，强调了在病理生理相关条件下使用精确方法来操纵乳酸化水平的必要性。乳酸化是一种新型蛋白质翻译后修饰，最早于2019年通过肽免疫沉淀与HPLC-MS/MS分析相结合被鉴定。这种修饰最早被发现与癌细胞和巨噬细胞中通过表观遗传调节对基因转录的调节有关。乳酸化的发现为理解Warburg效应的功能意义提供了一条新途径，因为乳酸是这种修饰的关键驱动因素。随后的研究表明，乳酸化发生在多种蛋白质上，包括组蛋白和非组蛋白，并且与不同的生理和病理背景有关。本文讨论了癌症乳酸化研究中当前的主要发现和未解决的问题，并进一步提出了潜在的策略来证实这种修饰的功能研究。高乳酸水平驱动乳酸化乳酸化发生在蛋白质的赖氨酸残基，包括组蛋白和非组蛋白。迄今为止，已在各种癌细胞中鉴定出1000多种乳酸化蛋白。乳酸化的主要驱动因素是乳酸，乳酸水平升高（在癌细胞中观察到的10至 30 mM）是乳酸化形成所必需的。这表明任何影响糖酵解的因素，特别是乳酸脱氢酶A（LDHA）的活性，都可以调节乳酸化水平。然而，尽管乳酸浓度高，但发生乳酸化的蛋白质比例相对较低，在总靶蛋白库中观察到的乳酸化不到 ∼10%。这表明由于非经典酶活性，乳酸化可能发生效率低下。作为一种手性化合物，赖氨酸 L-乳酸化和 D-乳酸化均已被鉴定。然而，赖氨酸 L-乳酸化是体内的主要异构体，因为 D-乳酸化是由涉及乳酸谷胱甘肽的非酶促过程产生的，仅在乙二醛酶系统受损时观察到。参与乳酸化的底物和酶基于乳酸化与与组蛋白乙酰化的相似性，乳酸-CoA被认为是乳酸化的底物。支持乳酸-CoA作为底物的证据包括两个关键观察结果：（1）乳酸-CoA水平与乳酸化呈正相关（2）组蛋白乙酰转移酶p300在体外使用乳酸-CoA进行乳酸化修饰。然而，乳酸辅酶 A 的酶源仍然未知（图1）。值得注意的是，癌细胞中乳酸-CoA的内源性水平极低，约为0.011 pmol/106个细胞，比哺乳动物细胞中的乙酸-CoA水平低约1,000倍。丙氨酸-tRNA合成酶AARS1和AARS2充当乳酸传感器和乳酸转移酶，可使多种蛋白质（包括p53、YAP和线粒体蛋白质）乳酸化。然而，与乙酰转移酶不同，AARS1直接使用乳酸作为底物，而不是乳酸-CoA。乳酸与人AARS1结合的Kd 值范围为2-35 μM，而癌细胞中的乳酸浓度可以达到10-30 mM，因此AARS1很可能在体内介导乳酸化中起主要作用。一些脱乙酰酶，如HDAC1-3和SIRT1-3，具有去乳酸化活性。然而，这些酶的主要功能是脱乙酰化，它们并不是乳酸化所特有的。图1. 参与乳酸化的酶和底物乳酸化的生物学意义：基因转录和蛋白质功能据报道的乳酸化功能可以根据修饰是发生在组蛋白还是非组蛋白中来大致分类。组蛋白乳酸化被认为通过表观遗传机制调节基因转录，然而目前还不清楚组蛋白乳酸化是否普遍抑制或增强基因表达。此外，虽然已经报道了组蛋白乳酸化的潜在writer和eraser，但相应的reader仍然未知。非组蛋白乳酸化被认为可以增强或抑制这些蛋白质的功能。例如，AARS1感知乳酸并转位到细胞核中以乳酸化YAP，维持其核定位并促进YAP激活；AARS1 介导的p53乳酸化抑制其相分离、DNA结合和转录激活，从而促进肿瘤发生。乳酸化也通过促进癌症中的 DNA 修复与化疗耐药有关。例如，负责维持基因组稳定性的MRE11-RAD50-NBS1（MRN）复合物的关键组分MRE11和NBS1都能发生乳酸化，对于复合物的形成和随后的DNA修复至关重要。图2. 乳酸化促进肿瘤发生和化疗耐药的机制总结明确乳酸化生物学功能面临的挑战乳酸化的特异性和效率较低首先，蛋白质乳酸化比例较低，使得很难区分乳酸化是起主要调节作用还是仅仅是其他代谢过程的次要结果。其次，目前尚不清楚乳酸化和去乳酸化是由少数特定酶还是更广泛的酶介导。第三，用于研究乳酸化的分析可能无法准确反映体内环境的条件，例如，一些研究中使用的乳酸-CoA浓度远高于细胞中通常发现的浓度，这可能会扭曲结果并导致高估乳酸化在细胞过程中的作用。缺乏操纵乳酸化的特异性工具研究乳酸化的常用方法及其局限性如下：（1）赖氨酸残基上乳基化位点点突变可能会改变蛋白质的内在特性并消除同一位点的其他PTM，尤其是乙酰化；（2）乳酸补充或LDHA抑制，可广泛影响乳酸化以外的细胞过程，例如氧化还原平衡和免疫逃避/抑制；（3）抑制糖酵解的上游调节因子，这可能导致比LDHA 抑制更广泛的副作用；（4）具有吡咯赖氨酰-tRNA合成酶的正交翻译系统，这是位点特异性乳酸化的强大工具，其局限性是乳酸化水平无法精确控制，无法反映真实的病理生理条件。图3. 乳酸化功能研究的注意事项验证乳酸化真实功能的研究策略为了阐明乳酸化的真正功能，开发能够在病理生理条件下精确和特异性地专门操纵乳酸化水平的不同方法至关重要。（1）具有吡咯赖氨酰-tRNA 合成酶的诱导型正交翻译系统以剂量依赖性方式选择性提高乳酸化水平。（2）使用AARS1变体的敲入模型特异性抑制乳酸化形成。小结尽管乳酸化具有潜在的重要性，但证明其与特定表型之间存在因果关系的明确证据仍有待进一步阐明。因此，开发能够精确、特异性地操纵病理生理条件下乳酸化水平的方法将更清楚地了解乳酸化在癌症中的作用。

临床结果

2024-10-21

·生物制药小编

5条肿瘤代谢通路

即使在氧充分的条件下（有氧糖酵解/Warburg效应），癌细胞上调葡萄糖的糖酵解途径形成乳酸，这个过程被认为是恶性肿瘤的标志。代谢活跃的癌细胞导致营养消耗、缺氧、酸性、有毒的代谢物富集的肿瘤微环境，抑制免疫系统。肿瘤细胞代谢与肿瘤微环境（Nat Rev Cancer . 2020 Sep;20(9):516-531）本文简介肿瘤细胞代谢调节的5条信号通路。其他代谢相关文章，请点击下面链接阅读 23种代谢产物与肿瘤免疫 T细胞代谢与功能的关系 1. Hippo Pathway Hippo通路控制细胞增殖、器官大小和组织稳态。它由MAPK家族、MST1/2、LATS1/2以及转录共激活因子YAP和TAZ组成。当该通路被激活时，上游信号磷酸化并激活MST1/2和LATS1/2，从而磷酸化YAP/TAZ。因此，YAP/TAZ通过14-3-3蛋白被隔离在细胞质中，并被E3连接酶β-TRCP降解。 Annu Rev Pathol. 2021 January 24; 16: 299–322 然而，当Hippo信号通路关闭时，YAP/TAZ易位到细胞核，与转录增强相关域(TEAD)转录因子结合，诱导致癌靶基因的表达。 Hippo通路受到广泛的上游调控因子的调控，包括细胞-细胞接触、来自周围环境刺激、Wnt信号传导、GPCR-配体相互作用和各种细胞应激条件。 YAP/TAZ促进糖酵解和谷氨酸代谢 YAP/TAZ活性在许多类型的癌症中都是过度活跃。hHippo通路作为细胞生长的主调节因子，参与了多种代谢过程。YAP/TAZ活性通过直接和间接提高糖酵解酶活性来促进糖酵解。特别是，YAP/TAZ的活性增加了TEAD对GLUT3的表达，并通过FOXC2诱导了HK2的表达。YAP/TAZ还通过Hedgehog信号通路促进LncRNABCAR4的表达，上调HK2和PFKFB3。YAP/TAZ增强谷氨酰胺代谢，增加乳腺癌细胞中谷氨酰胺转运体SLC1A5和SLC7A5的表达。YAP/TAZ和TEAD通过表达氨基酸转运体上调谷氨酰胺和氨基酸代谢。YAP/TAZ诱导谷氨酰胺酶和转氨酶的表达，包括GOT1和PSAT1，它们产生NEAAs和TCA循环中间体。YAP/TAZ积累脂质，直接调节胆汁酸成分，从而增强癌细胞的转移潜能。葡萄糖增强YAP/TAZ的活性细胞周期进程和细胞增殖由营养物质浓度决定。葡萄糖代谢对YAP/TAZ活性有显著影响。高糖水平增加了HSP的葡萄糖通量，产生用于糖基化的UDP-GlcNAc。因此，丰富的葡萄糖诱导YAP O-GlcNAcylation，干扰LATS和βTrCP的相互作用，进而增强YAP/TAZ的活性。在胰腺癌和肝癌中，YAP被O-GlcNAcylation过度激活。 LATS2的糖基化通过干扰乳腺癌中LATS2和MOB1的相互作用来抑制其活性。相反，葡萄糖剥夺诱导的能量应激通过hippo依赖和非依赖的机制抑制YAP/TAZ活性。能量传感器AMPK随着ATP的减少而被激活。AMPK直接磷酸化YAP的丝氨酸61和丝氨酸94，从而阻断YAP-TEAD的相互作用。AMPK通过AMOTL1磷酸化和激活间接抑制YAP。外部激素水平可以调节Hippo通路。脂质激素，如溶血磷脂酸和鞘氨醇-1-磷酸，通过GPCRs抑制该通路，肽激素胰高血糖素增加血糖水平，通过cAMP和PKA激活Hippo通路。脂肪增强YAP/TAZ的活性亚细胞脂质成分也可以调节Hippo通路激酶。SREBP是Hippo通路的上游调控因子。当SREBP被激活时，甲羟戊酸途径增强了RhoAGTPase的香叶酰化。RhoA是一个f-actin的细胞骨架调节因子，而f-actin是一个成熟的LATS激酶的上游因子。因此，癌细胞中脂肪酸代谢的增加会异常激活RhoA，并通过抑制LATS来增强YAP/TAZ的活性。有趣的是，YAP/TAZ在血液系统恶性肿瘤中几乎不表达，而YAP的强制表达已被证明可以介导肿瘤抑制功能。 2. PI3K-AKT/mTOR Pathway 在正常细胞中，细胞的增殖和合成代谢受到外部生长因子（如胰岛素和激素）的微妙调节，PI3K-AKT-mTOR通路是其中一条重要通路。 PI3K/AKT信号通路调节代谢酶。在被胰岛素激活后，AKT通过磷酸化GSK3来抑制糖原合成途径。PI3K/AKT通过代谢酶的翻译后修饰（如磷酸化、糖基化）直接或间接上调糖酵解。例如，AKT磷酸化并激活AS160蛋白，从而增强了GLUT的膜运输。AKT通过抑制磷酸化直接抑制TXNIP，通过抑制内吞作用增加GLUT1/4的膜表达。 AKT还提高了糖酵解酶的效率。AKT通过增加HK2的线粒体整合来磷酸化并激活HK2。AKT使PFKFB磷酸化；这种变化催化果糖-6-磷酸到F-2,6-BP，从而提高糖酵解。AKT信号通路也通过HIF-1α转录因子促进糖酵解。HIF-1激活一些糖酵解组分，包括GLUT。HIF-1诱导LDH促进乳酸分泌和有氧糖酵解。 PI3K/AKT信号通路上调谷氨酰胺和脂肪酸代谢。AKT通过mTORC1增加Myc的翻译，并通过GSK3和FOXO3A抑制Myc的降解。由于MYC调节谷氨酰胺代谢，MYC的激活增加了细胞氮的供应。因此，AKT促进了核苷酸的合成。癌细胞需要从头脂质合成来维持和供应持续的无限细胞分裂所需的膜成分。AKT通过直接磷酸化脂质合成的第一个酶ACLY，影响脂质的新生生物合成过程，从而提高酶的效率。AKT通过ACLY调控增加各种癌症类型中的组蛋白乙酰化 AKT诱导的mTORC1激活增强了SREBP家族的翻译和切割加工。AKT介导的GSK3抑制进一步阻止了SREBP1的降解。因此，了解通过PI3K/AKT信号通路的代谢重编程将阐明PI3K抑制剂对癌症治疗的有效治疗替代方案。 3. Myc Pathway 转录因子c-Myc通过MAX调控基因表达，是癌细胞中最过度活跃的基因之一，位于生长相关信号通路(如EGFR、AKT和GPCRs)的交叉点。 Myc调节与葡萄糖、谷氨酰胺和脂肪酸代谢相关的基因的表达。Myc通过上调糖酵解和谷氨酰胺水解来增强癌细胞的代谢重。Myc诱导许多糖酵解酶(如GLUT、HK2和PFK)，它们催化糖酵解过程相应步骤。 MYC癌基因的激活驱动谷氨酰胺的优先代谢向TCA循环添补反应（Anaplerosis）和随后的氧化磷酸化。MYC癌基因表达的缺失增加了线粒体代谢对葡萄糖的依赖。 4. p53 Pathway P53是最著名的肿瘤抑制基因之一，它影响细胞过程，包括凋亡、细胞周期进程和代谢。p53在细胞应激条件下被激活，如DNA损伤和营养剥夺。根据应激源的类型和强度，它决定了是发生适应还是细胞死亡。p53在转录、翻译和翻译后水平上被调节。p53的稳定性受E3连接酶MDM2的调控。 AMPK磷酸化，乙酰化，从而在能量应激条件下稳定p53。通过上调MDM2来促进p53的降解，p53诱导一个负反馈回路来维持稳态。 p53调节代谢（Cancers 2021, 13, 133） P53减少有氧糖酵解，上调线粒体分解代谢过程，包括脂肪酸氧化(FAO)和OXPHOS；p53转录抑制GLUT1和GLUT4的表达，抑制葡萄糖摄取；抑制TCA循环；增加脂肪酸氧化；增加氧化磷酸化（OXPHOS），积累NADH和FADH2。 5. LKB1/AMPK Pathway AMPK是一种保守性良好的能量传感激酶。AMPK抑制合成代谢途径（脂肪酸合成、mTOR途径），促进分解代谢（糖酵解、Krebs循环、磷酸戊糖途径、脂肪酸氧化和自噬）的细胞过程。因此，AMPK的激活允许细胞承受细胞能量应激条件。与其他代谢蛋白不同，AMPK的调控依赖于AMP和ADP的细胞浓度，但独立于其他代谢中间体。AMP/ATP比值的增加导致AMP相互作用，随后是AMPK的构象变化。在癌症的背景下，应激环境下的AMPK激活，包括缺氧和能量或营养剥夺，赋予了各种癌症的应激抵抗特性。 *红色箭头（激活上调）（Oxid Med Cell Longev . 2019 Oct 31;2019:8730816.） AMPK是一种致癌蛋白还是肿瘤抑制蛋白仍有待确定。在临床环境中，AMPK激活剂，包括2型糖尿病药物二甲双胍和AICAR，被用于抑制癌细胞增殖；然而，AMPK也通过促进原蛋白抗性、迁移和转移作为致癌蛋白。 ACC是AMPK的一个成熟的靶点。ACC在脂肪酸从头合成过程中，ACC介导乙酰辅酶A转化为丙二酰辅酶A。AMPK通过抑制ACC磷酸化来减少ATP的消耗。AMPK降低的脂肪酸合成通量降低了NADPH的消耗。为了满足细胞对脂质代谢物的需求，AMPK通过CD36和其他脂质转运体上调脂肪酸的摄取来维持脂质稳态。蛋白质翻译是高度耗能的，并使用多种合成代谢途径，包括PPP和谷氨酰胺水解。AMPK通过抑制mTORC1和翻译机制，允许癌细胞适应恶劣的营养条件，如葡萄糖剥夺。主要参考文献 Jordan H. Driskill et al，The Hippo Pathway in Liver Homeostasis and Pathophysiology. Annu Rev Pathol. 2021 January 24; 16: 299–322 Robert D. Leone and Jonathan D. Powell, Metabolism of immune cells in cancer, Nat Rev Cancer . 2020 Sep;20(9):516-531 Tambay, V.; Raymond, V.-A.; Bilodeau, M. MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype. Cancers 2021, 13, 4484 : Lahalle, A.; Lacroix, M.; De Blasio, C.; Cissé, M.Y.; Linares, L.K.; Le Cam, L. The p53 Pathway and Metabolism: The Tree That Hides the Forest. Cancers 2021, 13, 133 Francesco Ciccarese et al. LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective,Oxid Med Cell Longev . 2019 Oct 31;2019:8730816.

临床结果

2024-10-06

·生物探索

Cell Rep Med | 余发星团队报道胸膜间皮瘤基因治疗新策略

引言胸膜间皮瘤是一种罕见且高度恶性的肿瘤，起源于胸膜表面的间皮细胞，通常与石棉暴露密切相关【1】。现阶段针对胸膜间皮瘤的临床治疗主要以姑息疗法为主。尽管免疫检查点抑制剂等免疫疗法能在一定程度上改善患者的生存状况，但整体疗效有限，患者的中位总生存期仅约为18个月，预后不理想。因此，亟需进一步探索和开发新的策略用于胸膜间皮瘤的治疗。近年来的研究表明，胸膜间皮瘤的发病机制涉及多种抑癌基因的失活突变。胸膜间皮瘤患者样本的全外显子测序结果显示，NF2、BAP1、CDKN2A/B和TP53等多种抑癌基因在患者中经常发生突变或缺失【2】。此外，LATS2失活突变在间皮瘤患者中也较为常见【2】。NF2和LATS2分别是Hippo抑癌信号通路中的重要接头蛋白和激酶，这些基因的高频突变表明Hippo信号通路在胸膜间皮瘤的发生发展中发挥重要作用，提示Hippo信号通路有潜力成为胸膜间皮瘤治疗靶点。 2024年10月4日，复旦大学生物医学研究院/附属儿科医院余发星团队在Cell Reports Medicines上发表了题为“Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo”的研究论文。该研究报道了一种基于腺相关病毒（AAV）的胸膜间皮瘤基因治疗新策略，并通过小鼠胸膜间皮瘤的遗传肿瘤模型验证了该策略的有效性。 Hippo信号通路通常被视为是一个“线性”激酶级联反应，即MST1/2激酶和MAP4Ks激酶通过作用于LATS1/2激酶来调控YAP/TAZ转录共激活因子【3】。为深入理解LATS1/2和YAP/TAZ如何整合上游信号，余发星团队系统梳理了该信号通路的核心分子网络，提出了HPO1和HPO2两个双信号模块架构，其中WWC和NF2分别介导两个信号模块的活化，并且基于WWC蛋白的作用机制开发了SuperHippo迷你基因分子工具【4,5】。 NF2在胸膜间皮瘤中的失活突变频率高达40%，提示HPO2信号在该疾病中具有潜在调节作用，这一观点已在前人研究中得到验证。本研究通过间皮瘤细胞系和小鼠遗传模型探究了HPO1信号（WWC和SAV1）在间皮瘤中的功能，结果表明：当HPO1信号缺失后，间皮瘤细胞的体外增殖和体内成瘤能力明显增强；而当HPO1和HPO2信号同时缺失时，小鼠胸膜间皮明显增厚并呈现胸膜间皮瘤的特征。因此，HPO1信号同样参与胸膜间皮瘤的疾病进程，活化HPO1信号应该具有抗癌潜力。的确，在小鼠胸膜间皮瘤遗传模型中过表达SuperHippo能够显著抑制肿瘤进展。基于这些发现，研究团队提出一种“双管齐下”的膜间皮瘤治疗新策略：一方面通过回补NF2恢复HPO2的正常功能，另一方面通过过表达SuperHippo使HPO1超活化，同时提升HPO1和HPO2活性，最大程度地激活Hippo信号通路，从而充分发挥其抑癌功能。由于NF2和SuperHippo基因较小，能够被同一AAV病毒载体携带并表达，实现“一石二鸟”的功效。研究还表明，AAV6可以有效感染间皮细胞，团队最终制备了AAV6-SuperHippo-NF2 病毒用于临床前研究。在Nf2/Trp53小鼠胸膜间皮瘤模型中，该病毒显著抑制了肿瘤进展并延长了小鼠生存期，展现了显著的抗癌潜力。综上，该研究通过胸膜间皮瘤的细胞系及小鼠模型验证了Hippo信号通路，特别是HPO1信号模块，在胸膜间皮瘤中的抑癌作用。此外，研究还提出了一种全新的基因治疗新方案，并在小鼠遗传模型中验证了其可行性。这些发现为通过基因治疗靶向Hippo信号通路治疗胸膜间皮瘤提供了概念性验证，并为后续的临床转化研究奠定了基础。参考文献 1. Febres-Aldana CA, Fanaroff R, Offin M, et al. Annu Rev Pathol, 2024, 19:11-42. 2. Badhai J, Pandey GK, Song JY, et al. Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice. J Exp Med. 2020, 217(6):e20191257. 3. Yu FX, Zhao B, Guan KL. Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell. 2015, 163(4):811-28. 4. Qi S, Zhu Y, Liu X, Li P, Wang Y, Zeng Y, Yu A, Wang Y, Sha Z, Zhong Z, Zhu R, Yuan H, Ye D, Huang S, Ling C, Xu Y, Zhou D, Zhang L, Yu FX. WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy. Mol Cell. 2022, 82(10):1850-1864.e7. 5. Qi S, Zhong Z, Zhu Y, Wang Y, Ma M, Wang Y, Liu X, Jin R, Jiao Z, Zhu R, Sha Z, Dang K, Liu Y, Lim DS, Mao J, Zhang L, Yu FX. Two Hippo signaling modules orchestrate liver size and tumorigenesis. EMBO J. 2023, 42(11):e112126. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00493-2 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

免疫疗法基因疗法