更新于：2024-05-01

PDK1

磷酸肌醇依赖性激酶1

更新于：2024-05-01

基本信息

别名

3-phosphoinositide dependent protein kinase 1、3-phosphoinositide-dependent protein kinase 1、hPDK1

+ [3]

简介

Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.

关联

项与 PDK1 相关的药物

Tovorafenib

靶点

PDK1 x Raf kinase

作用机制

PDK1抑制剂 [+1]

在研机构

Day One Biopharmaceuticals, Inc. [+1]

原研机构

Sunesis Pharmaceuticals, Inc.

在研适应症

BRAF 融合或重排阳性的低级别胶质瘤 [+13]

非在研适应症

BRAF V600E 突变阳性低级别胶质瘤 [+2]

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2024-04-23

PH-427

靶点

Akt x PDK1

作用机制

AKT基因抑制剂 [+1]

在研机构

Phusis Therapeutics, Inc.

原研机构

Phusis Therapeutics, Inc.

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

JX06

靶点-

作用机制

PDK1抑制剂

在研机构

中国科学院上海药物研究所

原研机构

中国科学院上海药物研究所

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 PDK1 相关的临床试验

NCT05828069 / Recruiting临床2期IIT

Phase 2 Study of Tovorafenib (DAY101) in Relapsed and Refractory Langerhans Cell Histiocytosis

This phase II trial tests the safety, side effects, best dose and activity of tovorafenib (DAY101) in treating patients with Langerhans cell histiocytosis that is growing, spreading, or getting worse (progressive), has come back (relapsed) after previous treatment, or does not respond to therapy (refractory). Langerhans cell histiocytosis is a type of disease that occurs when the body makes too many immature Langerhans cells (a type of white blood cell). When these cells build up, they can form tumors in certain tissues and organs including bones, skin, lungs and pituitary gland and can damage them. This tumor is more common in children and young adults. DAY101 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Using DAY101 may be effective in treating patients with relapsed or refractory Langerhans cell histiocytosis.

开始日期2024-03-28

申办/合作机构

National Cancer Institute

NCT06381570 / Recruiting早期临床1期IIT

VICTORY: A Pilot Study to Investigate Safety and Efficacy of Weekly Combination of Intravenous Vinblastine With Oral Type II RAF Inhibitor Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas

This is a Pilot, multicenter, open-label study of patients less than or equal to 25 years, with recurrent or progressive LGG harboring a CRAF or BRAF alteration, including BRAF V600 mutations and KIAA1549: BRAF fusions. Patients with BRAF or CRAF alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories.
The study will be conducted in two sequential phases:
Phase A: A Feasibility (combination dose finding) phase, followed by Phase B: An Efficacy phase. The maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of the combination as determined in Phase A would be the dose used in Phase B. The patients on Phase A who were below the MTD/RP2D would be eligible for intra-patient dose escalation to MTD/RP2D subject to criteria outlined later

开始日期2024-03-21

申办/合作机构

The Hospital for Sick Children

[+1]

NCT05566795 / Recruiting临床3期

LOGGIC/FIREFLY-2: A Phase 3, Randomized, International Multicenter Trial of DAY101 Monotherapy Versus Standard of Care Chemotherapy in Patients With Pediatric Low-Grade Glioma Harboring an Activating RAF Alteration Requiring First-Line Systemic Therapy

This is a 2-arm, randomized, open-label, multicenter, global, Phase 3 trial to evaluate the efficacy, safety, and tolerability of DAY101 monotherapy versus standard of care (SoC) chemotherapy in patients with pediatric low-grade glioma (LGG) harboring an activating rapidly accelerated fibrosarcoma (RAF) alteration requiring front-line systemic therapy.

开始日期2023-02-27

申办/合作机构

Day One Biopharmaceuticals, Inc.

100 项与 PDK1 相关的临床结果

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100 项与 PDK1 相关的转化医学

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0 项与 PDK1 相关的专利（医药）

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2,738

项与 PDK1 相关的文献（医药）

2024-02-21·Acta pharmacologica Sinica

Proteomics analysis of histone deacetylase inhibitor-resistant solid tumors reveals resistant signatures and potential drug combinations.

Article

作者: Bing-Bing Hao ; Ke Ma ; Jun-Yu Xu ; Ru-Feng Fan ; Wen-Si Zhao ; Xing-Long Jia ; Lin-Hui Zhai ; SangKyu Lee ; Dong Xie ; Min-Jia Tan

Histone deacetylase inhibitors (HDACis) are important drugs for cancer therapy, but the indistinct resistant mechanisms of solid tumor therapy greatly limit their clinical application. In this study we conducted HDACi-perturbated proteomics and phosphoproteomics analyses in HDACi-sensitive and -resistant cell lines using a tandem mass tag (TMT)-based quantitative proteomic strategy. We found that the ribosome biogenesis proteins MRTO4, PES1, WDR74 and NOP16 vital to tumorigenesis might regulate the tumor sensitivity to HDACi. By integrating HDACi-perturbated protein signature with previously reported proteomics and drug sensitivity data, we predicted and validated a series of drug combination pairs potentially to enhance the sensitivity of HDACi in diverse solid tumor. Functional phosphoproteomic analysis further identified the kinase PDK1 and ROCK as potential HDACi-resistant signatures. Overall, this study reveals the potential HDACi-resistant signatures and may provide promising drug combination strategies to attenuate the resistance of solid tumor to HDACi.

2024-02-21·Molecular and cellular biochemistry

Identification of key genes of diabetic cardiomyopathy in hiPSCs-CMs based on bioinformatics analysis.

Article

作者: Shuo An ; Hongchen Bi ; Xiaoli Luo ; Caiying Zhu ; Min Wang ; Aiming Pang ; Yujie Cui

Diabetic cardiomyopathy (DbCM) is one of the most common vascular complications of diabetes, and can cause heart failure and threaten the life of patients. The pathogenesis is complex, and key genes have not fully identified. In this study, bioinformatics analysis was used to predict DbCM-related gene targets. Published datasets from the NCBI Gene Expression Omnibus with accession numbers GSE62203 and GSE197850 were selected for analysis. Differentially expressed genes (DEGs) were identified by the online tool GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID online database. Protein-protein interaction network construction and hub gene identification were performed using STRING and Cytoscape. We used 30 mM and 1 μM hydrocortisone-stimulated AC16 cells as an in vitro model of diabetic cardiomyopathy. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression levels of hub genes. A total of 73 common DEGs were identified in both datasets, including 47 upregulated and 26 downregulated genes. GO and KEGG pathway enrichment analyses revealed that the DEGs were significantly enriched in metabolism, hypoxia response, apoptosis, cell proliferation regulation, and cytoplasmic and HIF signalling pathways. The top 10 hub genes were LDHA, PGK1, SLC2A1, ENO1, PFKFB3, EGLN1, MYC, PDK1, EGLN3 and BNIP3. In our in vitro study, we found that PGK1, SLC2A1, PFKFB3, EGLN1, MYC, EGLN3 and BNIP3 were upregulated, ENO1 was downregulated, and LDHA was unchanged. Except for PGK1 and ENO1, these hub genes have been previously reported to be involved in DbCM. In summary, we identified DEGs and hub genes and first reported PGK1 and ENO1 in DbCM, which may serve as potential candidate genes for DbCM targeted therapy.

2024-02-15·Heliyon

The metabolic role of the CD73/adenosine signaling pathway in HTR-8/SVneo cells: A Double-Edged Sword?

Article

作者: Guangmin Song ; Dan Zhang ; Jianan Zhu ; Andi Wang ; Xiaobo Zhou ; Ting-Li Han ; Hua Zhang

The ecto-5'-nucleotidase (CD73)/adenosine signaling pathway has been reported to regulate tumor epithelial-mesenchymal transition (EMT), migration and proliferation. However, little is known about the metabolic mechanisms underlying its role in trophoblast proliferation and migration. In this study, we aimed to investigate the metabolic role of the CD73/adenosine signaling pathway on the proliferation and migration of trophoblast. We found that CD73 levels were upregulated in preeclamptic placentas compared with the placentas of normotensive pregnant women. EMT and migration of HTR-8/SVneo cells were enhanced when treated with a CD73 inhibitor (100 μM) in vitro. Conversely, excessive adenosine (25 or 50 μM) suppressed trophoblast cell EMT, migration and proliferation. RNA-seq, metabolomics and seahorse findings showed that adenosine treatment resulted in increased expression of PDK1, suppression of aerobic respiration, glycolysis and amino acids synthesis, as well as increased utilization of short-chain fatty acids (SCFAs). Furthermore, the ¹³C-adenosine isotope tracking experiment demonstrated that adenosine served as a carbon source for the tricarboxylic acid (TCA) cycle. Our results reveal the role of adenosine in regulating trophoblast energy metabolism is like a double-edged sword - either inhibiting aerobic respiration or supplementing carbon sources into metabolic flux. CD73/adenosine signaling regulated trophoblast EMT, migration, and proliferation by modulating energy metabolism. This study indicates that CD73/adenosine signaling potentially plays a role in the occurrence of placenta-derived diseases, including preeclampsia.

项与 PDK1 相关的新闻（医药）

2024-01-31

·生物探索

Cell Rep Med | 复旦大学余科达/邵志敏等团队合作发现三阴性乳腺癌的潜在治疗新策略

引言癌症干细胞(CSCs)是三阴性乳腺癌(TNBC)细胞中最棘手的亚群，其复发风险高，预后差。然而，根除CSCs仍然很困难。2024年1月29日，复旦大学余科达及邵志敏等团队合作在Cell Reports Medicine (IF 14.3)在线发表题为“Targeting EMSY-mediated methionine metabolism is a potential therapeutic strategy for triple-negative breast cancer”的研究论文，该研究整合了TNBC队列(n = 360)的多组学数据，以确定CSCs的重要标志物，研究发现EMSY，诱导BRCAness表型，优先在乳腺CSCs中表达，促进ALDH+细胞富集，并与不良无复发生存率呈正相关。在机制上，EMSY竞争性地结合对KDM5B酶活性至关重要的Jmjc结构域，重塑蛋氨酸代谢，并以H3K4甲基化依赖的方式促进CSC自我更新和肿瘤发生。此外，EMSY在TNBC细胞中的积累使它们对针对体细胞的PARP抑制剂和针对CSCs的蛋氨酸剥夺敏感。这些发现表明，临床相关的CSCs清除可以通过针对CSCs氨基酸代谢特异性脆弱性的策略来实现。三阴性乳腺癌(TNBC)是一种生物学和临床异质性疾病，约占诊断乳腺癌的12%-17%，由于早期复发率高和治疗选择有限，预后非常糟糕。之前的多组学研究包括465名中国复旦大学上海癌症中心(FUSCC) TNBC患者，描述了一个强大的分类系统，包括四个具有不同分子特征的转录组亚型:间充质样(MES)、腔内雄激素受体(LAR)、免疫调节(IM)和基底样和免疫抑制(BLIS)亚型。进一步揭示了每种转录组亚型的潜在治疗靶点，并对转移性TNBC进行了一项总称试验(FUTURE, ClinicalTrials.gov, NCT03805399)，以评估与这些靶点相关的临床疗效FUTURE试验显示出令人鼓舞的客观缓解率(ORR)为29%，明显高于传统化疗的ORR(5%-15%)。然而，相应的靶向治疗的治疗结果并没有达到预期，特别是对于MES亚型。因此，需要更深入地了解MES子类型以识别新目标。基因表达谱显示，MES亚型在乳腺干细胞通路中富集，并表现出癌症干细胞(CSCs)的特征。CSCs，也被称为乳腺肿瘤启动细胞，是肿瘤细胞的一个亚群，存在于肿瘤块中，具有肿瘤发生、自我更新、耐化疗、复发和转移的特点。因此，特异性消除CSCs可能是最重要的治疗策略之一。自20世纪50年代以来，已有文献证明癌细胞依靠糖酵解而不是氧化磷酸化(OXPHOS)来产生能量，氧化磷酸化是一种更有效的产生ATP的过程。相比之下，最近的一些研究表明，来自多种肿瘤类型(乳腺癌、胶质母细胞瘤、黑色素瘤和胰腺癌)的CSCs依赖于OXPHOS，并且比更成熟的癌细胞具有更低的糖酵解储备。除了对OXPHOS的选择性依赖外，一些研究还记录了CSCs的其他特异性代谢特性。其中包括一些乳腺CSC (BCSC)亚群中脂肪酸β氧化水平升高，乳腺癌中PDK1依赖性代谢重编程，活性氧水平低和谷胱甘肽水平升高，对线粒体翻译和呼吸成分的优先依赖、和特定氨基酸代谢的激活增加。总之，这些数据表明，了解恶性干细胞独特的代谢特性可能是改进CSCs治疗的核心。模式图（Credit: Cell Reports Medicine）EMSY是原癌基因的产物，其位点在乳腺癌和其他人类癌症中经常被扩增。EMSY和CCND1协同工作，促进肺癌和ER阳性他莫昔芬治疗的发病机制。EMSY与BCRA2物理相互作用并抑制BRCA2活性，其过表达诱导BRCAness表型。最新研究表明，EMSY在keap1突变的非小细胞肺癌(NSCLC)中积累可诱导同源重组修复(HRR)缺陷并抑制干扰素反应，从而使其对PARP抑制剂(PARPi)和STING激动剂敏感。此外，EMSY是几个染色质重塑复合体的一部分，并作为干扰素刺激基因的负调节因子。尽管在小鼠异种移植模型中，EMSY在乳腺肿瘤细胞中的过表达促进了肿瘤的生长和转移，但对于EMSY在乳腺CSCs中的功能知之甚少。该研究报道了EMSY介导的蛋氨酸代谢调节的分子基础及其对TNBC肿瘤发生的贡献。值得注意的是，作者提出并实验验证了一种使用奥拉帕尼(一种PARPi)和膳食中蛋氨酸剥夺的组合策略。该研究证明了肿瘤浸润性CSCs中代谢、组蛋白模式和功能谱之间的长期相互作用，这为将这些见解转化为通过靶向其独特的代谢需求来根除耐药CSCs的潜在策略奠定了基础。原文链接https://doi.org/10.1016/j.xcrm.2024.101396责编|探索君排版|探索君文章来源|“iNature”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Science最新发布：全世界最前沿的125个科学问题热文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Nature | 颠覆性发现：我们肠道微生物中隐藏的“奇异RNA碎片”

CSCO会议临床研究

2024-01-31

·生物制品圈

Cell子刊 | 复旦大学余科达/邵志敏等团队合作发现三阴性乳腺癌的潜在治疗新策略

摘要癌症干细胞(CSCs)是三阴性乳腺癌(TNBC)细胞中最棘手的亚群，其复发风险高，预后差。然而，根除CSCs仍然很困难。2024年1月29日，复旦大学余科达及邵志敏等团队合作在Cell Reports Medicine 在线发表题为“Targeting EMSY-mediated methionine metabolism is a potential therapeutic strategy for triple-negative breast cancer”的研究论文，该研究整合了TNBC队列(n = 360)的多组学数据，以确定CSCs的重要标志物，研究发现EMSY，诱导BRCAness表型，优先在乳腺CSCs中表达，促进ALDH+细胞富集，并与不良无复发生存率呈正相关。在机制上，EMSY竞争性地结合对KDM5B酶活性至关重要的Jmjc结构域，重塑蛋氨酸代谢，并以H3K4甲基化依赖的方式促进CSC自我更新和肿瘤发生。此外，EMSY在TNBC细胞中的积累使它们对针对体细胞的PARP抑制剂和针对CSCs的蛋氨酸剥夺敏感。这些发现表明，临床相关的CSCs清除可以通过针对CSCs氨基酸代谢特异性脆弱性的策略来实现。三阴性乳腺癌(TNBC)是一种生物学和临床异质性疾病，约占诊断乳腺癌的12%-17%，由于早期复发率高和治疗选择有限，预后非常糟糕。之前的多组学研究包括465名中国复旦大学上海癌症中心(FUSCC) TNBC患者，描述了一个强大的分类系统，包括四个具有不同分子特征的转录组亚型:间充质样(MES)、腔内雄激素受体(LAR)、免疫调节(IM)和基底样和免疫抑制(BLIS)亚型。进一步揭示了每种转录组亚型的潜在治疗靶点，并对转移性TNBC进行了一项总称试验(FUTURE, ClinicalTrials.gov, NCT03805399)，以评估与这些靶点相关的临床疗效FUTURE试验显示出令人鼓舞的客观缓解率(ORR)为29%，明显高于传统化疗的ORR(5%-15%)。然而，相应的靶向治疗的治疗结果并没有达到预期，特别是对于MES亚型。因此，需要更深入地了解MES子类型以识别新目标。基因表达谱显示，MES亚型在乳腺干细胞通路中富集，并表现出癌症干细胞(CSCs)的特征。CSCs，也被称为乳腺肿瘤启动细胞，是肿瘤细胞的一个亚群，存在于肿瘤块中，具有肿瘤发生、自我更新、耐化疗、复发和转移的特点。因此，特异性消除CSCs可能是最重要的治疗策略之一。自20世纪50年代以来，已有文献证明癌细胞依靠糖酵解而不是氧化磷酸化(OXPHOS)来产生能量，氧化磷酸化是一种更有效的产生ATP的过程。相比之下，最近的一些研究表明，来自多种肿瘤类型(乳腺癌、胶质母细胞瘤、黑色素瘤和胰腺癌)的CSCs依赖于OXPHOS，并且比更成熟的癌细胞具有更低的糖酵解储备。除了对OXPHOS的选择性依赖外，一些研究还记录了CSCs的其他特异性代谢特性。其中包括一些乳腺CSC (BCSC)亚群中脂肪酸β氧化水平升高，乳腺癌中PDK1依赖性代谢重编程，活性氧水平低和谷胱甘肽水平升高，对线粒体翻译和呼吸成分的优先依赖、和特定氨基酸代谢的激活增加。总之，这些数据表明，了解恶性干细胞独特的代谢特性可能是改进CSCs治疗的核心。机理模式图（图源自Cell Reports Medicine）EMSY是原癌基因的产物，其位点在乳腺癌和其他人类癌症中经常被扩增。EMSY和CCND1协同工作，促进肺癌和ER阳性他莫昔芬治疗的发病机制。EMSY与BCRA2物理相互作用并抑制BRCA2活性，其过表达诱导BRCAness表型。最新研究表明，EMSY在keap1突变的非小细胞肺癌(NSCLC)中积累可诱导同源重组修复(HRR)缺陷并抑制干扰素反应，从而使其对PARP抑制剂(PARPi)和STING激动剂敏感。此外，EMSY是几个染色质重塑复合体的一部分，并作为干扰素刺激基因的负调节因子。尽管在小鼠异种移植模型中，EMSY在乳腺肿瘤细胞中的过表达促进了肿瘤的生长和转移，但对于EMSY在乳腺CSCs中的功能知之甚少。该研究报道了EMSY介导的蛋氨酸代谢调节的分子基础及其对TNBC肿瘤发生的贡献。值得注意的是，作者提出并实验验证了一种使用奥拉帕尼(一种PARPi)和膳食中蛋氨酸剥夺的组合策略。该研究证明了肿瘤浸润性CSCs中代谢、组蛋白模式和功能谱之间的长期相互作用，这为将这些见解转化为通过靶向其独特的代谢需求来根除耐药CSCs的潜在策略奠定了基础。原文链接：https://doi.org/10.1016/j.xcrm.2024.101396识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

CSCO会议临床研究

2024-01-13

·生物探索

Gut | 中山大学郭剑平/匡铭揭示高脂肪饮食通过棕榈酰化和AKT的激活促进肝脏肿瘤的发生

作为代谢稳态的中心节点，PI3K-AKT通路是否以及如何导致高脂肪诱导的非酒精性脂肪性肝炎(NASH)和肝细胞癌(HCC)仍然是一个谜。2024年1月8日，中山大学郭剑平及匡铭共同通讯在Gut（IF=25）在线发表题为“High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT”的研究论文，该研究发现高脂肪饮食通过棕榈酰化和AKT的激活促进肝脏肿瘤的发生。通过筛选代谢物库，该研究发现PA通过促进棕榈酰修饰激活AKT，这是生长因子诱导AKT激活的必要步骤。在生物学上，高脂肪饮食可以促进AKT激酶活性，从而促进NASH和肝癌。从机制上讲，棕榈酰结合以不依赖PIP3的方式将AKT锚定在细胞膜上，部分原因是通过阻止AKT组装成非活性聚合物。棕榈酰转移酶ZDHHC17/24被表征为棕榈酰化AKT发挥致癌作用。有趣的是，抗肥胖药物奥利司他或特异性穿透肽可分别通过限制PA合成或抑制AKT修饰有效减弱AKT棕榈酰化和活化，从而拮抗肝脏肿瘤发生。该研究阐明了PA-ZDHHC17 /24介导的棕榈酰化对AKT的一种新的微调调节，并强调了通过限制PA饮食、限制PA合成或直接靶向AKT棕榈酰化来治疗肿瘤的策略。饮食不仅为肿瘤细胞不受控制的生长提供营养和基础，而且还促进信号转导，影响肿瘤的各个方面，因此饮食改变疗法最近已经实现，包括热量限制和低热量脂肪饮食。值得注意的是，高脂肪饮食(HFDs)主要与代谢性疾病相关，包括肥胖和癌症，其机制多样且尚不清楚。其中，棕榈油是最主要的膳食油来源之一，也是肥胖的主要原因之一，被认为是一种代谢性疾病，倾向于诱发肿瘤。值得注意的是，PA作为棕榈脂和动物脂肪油的主要成分，其代谢功能形成细胞质膜，与口腔肿瘤转移密切相关。同时，PA的活性产物棕榈酰辅酶A已被证明可诱导多种蛋白的棕榈酰修饰，如MC1R对紫外线诱导的黑色素瘤起作用，STAT3对IL-6诱导的Th17分化和抗病毒感染起作用，N-RAS对结肠癌起作用。然而，合成或食物摄取的PA积累是否以及如何参与肿瘤发生，特别是参与代谢稳态的器官，如肝脏，尚不清楚。HFD一直被认为是非酒精性脂肪性肝炎(NASH)的一个不减弱的危险因素，NASH是一种非酒精性脂肪性肝病(NAFLD)的晚期形式，现在也被称为代谢功能障碍相关的脂肪性肝炎。NASH涉及小叶炎症、纤维化和肝细胞膨胀，可发展为HCC。尽管自噬和免疫反应等多种潜在机制与NASH相关，但作为代谢稳态的中心节点，在脂肪生成和HCC进展中发挥重要作用的PI3K-AKT通路是否以及如何导致高脂肪诱导的NASH和HCC仍是一个谜。棕榈酰化增强AKT活性和致癌功能的模型（图源自Gut ）PI3K-AKT通路作为响应细胞外刺激的中心信号，在生理上对细胞生长、存活和代谢稳态起着关键作用，在病理上对糖尿病和肿瘤发生也起着关键作用。因此，AKT的调控，特别是在翻译后水平，已被广泛确立。值得注意的是，AKT PH结构域与PI3K生成的PIP3的结合被认为是通过PDK1介导的T308和mTORC2介导的S473磷酸化完全激活AKT的关键步骤。例如，泛素化、乙酰化和甲基化都有助于AKT与PIP3的结合，从而进一步激活PIP3。因此，PIP3相关酶的遗传改变，包括其激酶PIK3CA、磷酸酶PTEN及其上游调节蛋白，如RAS和EGFR，已在大约50%的不同类型的癌症中被观察到，这在很大程度上有助于PIP3的积累和随后的AKT激活。为此，针对PIK3CA-H1047R突变体的特异性抑制剂已被批准用于乳腺癌干预。然而，除了典型的PI3K-PIP3依赖性AKT激活外，AKT是否以及如何以PIP3独立的方式激活尚不清楚。该研究报道了从HFDs中积累PA或异常合成促进ZDHHC17 /24-以PIP3不依赖的方式催化棕榈酰化和激活AKT，导致NASH和肝脏肿瘤发生，并强调了靶向PA-ZDHHC-AKT轴治疗HCC的策略。参考文献：Bu L, Zhang Z, Chen J, Fan Y, Guo J, Su Y, et al. High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT. Gut. 2024 Jan 8:gutjnl-2023-330826. doi: 10.1136/gutjnl-2023-330826. Epub ahead of print. PMID: 38191266. 责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

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