SREBF1

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.

OXFORD, United Kingdom, Oct. 10, 2024 (GLOBE NEWSWIRE) -- MitoRx Therapeutics (MitoRx), a platform biotechnology company developing novel mitochondrial-targeted sulfide-donor therapeutics (mtH2SD) in obesity-related disorders and myopathies announces a publication in Elsevier’s prestigious biomedical sciences journal Pharmacological Research. The work led by collaborators at Jagiellonian University Medical College showed that in a preclinical mouse study involving high-fat diet (HFD)-induced obesity, the company’s mtH2SD compound AP39, significantly slowed the rate of gain in weight. This is the first comprehensive study designed to test whether mitochondrial sulfide donors could address weight gain and fatty liver (steatosis). Mounting evidence suggests that hydrogen sulfide is an important signalling molecule in the liver, regulating lipid metabolism and mitochondrial function, but its direct delivery to mitochondria had not been investigated as a therapeutic strategy in obesity-related metabolic disorders. This is what the Pharmacological Research paper examined. MitoRx’s CSO, Prof Matt Whiteman, and their Senior Discovery Chemist, Dr. Roberta Torregrossa, with co-inventor Dr. Mark Wood at the University of Exeter are co-authors on the paper. It showed that treatment with AP39 reduced weight gain in animals fed HFD by 32% at the end of the research. (1) AP39 is a versatile mtH2SD tool compound that mediates very large and statistically significant reductions in liver steatosis, large and significant reductions in triglycerides, reductions in de novo lipogenesis, reductions in inflammatory markers, and significant downregulation of known liver proteomic markers of weight gain and the development of obesity, indicating mtH2SD-mediated downregulation mTOR/SREBP-1/SCD1 pathway alleviates obesity. MitoRx is developing undisclosed next-generation mtH2SDs to take to the clinic. Importantly, this modality is both muscle protective including in a severe fibrotic muscle atrophy model and is also anti-obesogenic. With this double therapeutic benefit, MitoRx’s next-gen mtH2SDs could potentially address the loss of lean muscle mass which is a serious side effect of marketed GLP-1 receptor agonist drugs in general, especially with age. This approach could be applicable in sarcopenic (age-related muscle mass and strength loss) obesity while also addressing muscle wasting in obese patients in general. Dr. Jon Rees, Chief Executive Officer of MitoRx, said: “MitoRx is advancing its first-in-class mitochondriotropic platform initially focused on myopathies and is now applying it to obesity offering a small molecule anti-obesogenic which is also muscle protective. This latest publication provides solid pre-clinical evidence that AP39 substantially suppressed the gain of weight in HFD-fed animals, suggesting a new pathway to alleviate obesity, whilst avoiding the muscle wasting side-effects that blight GLP-1 receptor agonist drugs. Powerful international research collaborations like this, with the talented team at Jagiellonian University’s Faculty of Medicine, help speed therapeutic advances to patients.” Dr. Aneta Stachowicz, Department of Pharmacology at the Faculty of Medicine, Jagiellonian University Medical College, Poland, and lead author of the Pharmacological Research paper, said: “Having comprehensively demonstrated that mitochondrial-targeted sulfide donors alleviate weight gain and significantly reduce multiple markers of obesity, we mark the beginning of a new era in the development of an innovative therapeutic approach for metabolic disease through the modulation of mitochondrial sulfide-signalling.” Matt Whiteman, Professor of Experimental Therapeutics at the University of Exeter Medical School, UK, and co-author of the study added: We discovered impaired sulfide metabolism in overweight patients with type 2 diabetes in 2010 (2) and we noticed that this impairment was driven by the amount of fat tissue these individuals were carrying; an observation since confirmed by many others. These findings suggested that treating this impairment with mtH2SD could potentially treat diabetes, obesity and complications arising from having too much fat in the body. It is gratifying to now translate those observations toward clinically viable drugs with MitoRx References: (1): Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-Kappa-B signaling pathways. Pharmacological Research 209 (2024):107428https://doi-org.libproxy1.nus.edu.sg/10.1016/j.phrs.2024.107428 (2): Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia 53(8):1722-6 (2010). https://doi-org.libproxy1.nus.edu.sg/10.1007/s00125-010-1761-5 Company Contact (MitoRx) Jon Rees, CEOEmail: jon.rees@mitorxtherapeutics.com Phone: +44(0)7826 556622 Media Contact (Scius Communications for MitoRx) Katja Stout, Managing PartnerEmail: katja@sciuscommunications.com Phone: +44(0)7789 435990 University of Exeter Press Office  +44 (0)1392 722405 or 722062pressoffice@exeter.ac.uk Jagiellonian University Marcin Kubatrzecznik@uj.edu.pl About MitoRx TherapeuticsAt MitoRx our mission is to become the leading global developer of medicines arresting the progression of degenerative diseases driven by mitochondrial dysfunction. We are a preclinical stage biotechnology company developing our first-in-class first-in-target, mitochondriotropic therapeutics in obesity-related indications and myopathies. Located in Harwell, Oxford, we have raised £5.4m seed financing from investors including the UK Innovation & Science Seed Fund, the Fink Family Office, Oxford Technology Management, Empirical Ventures, Wren Capital and Longevitytech.fund, as well as angel investors. For more information visit our website at www.mitorxtherapeutics.com and follow us on LinkedIn. About the University of ExeterThe University of Exeter is a Russell Group university that combines world-class research with high levels of student satisfaction. Exeter has over 30,000 students and sits within the Top 15 universities in The Complete University Guide 2025, and tenth in the world in the Times Higher Education (THE) Impact Rankings. In the 2021 Research Excellence Framework (REF), more than 99% of our research were rated as being of international quality, and our world-leading research impact has grown by 72% since 2014, more than any other Russell Group university.https://www.exeter.ac.uk/ About Jagiellonian University The Jagiellonian University is the oldest higher education institution in Poland and one of the oldest in Europe. It was founded on 12 May 1364 by the Polish king Casimir the Great. The Jubilee year 2014 marked the 650th anniversary of this remarkable event. Since its very beginning, the Jagiellonian University has been an international institution. Today, the Jagiellonian University comprises 16 Faculties, where nearly 4 thousand academic staff conduct research and provide education to over 40 thousand students, within the framework of more than 80 different fields of study. The eminent researchers and state-of-the-art infrastructure make the JU one of the leading Polish scientific institutions, collaborating with major academic centres from all over the world. The Jagiellonian University is also home to about 150 student societies, where young researchers pursue their academic interests and develop friendships with people who share their passion. For more information visit our website at https://en.uj.edu.pl/en.

引言 衰老是癌症的重要风险因素，大多数肿瘤的确诊发生在50岁以上的个体 【1】。乳腺癌是女性中最常见的癌症，平均确诊年龄为62岁【2】，然而，目前针对老龄动物模型的研究仍然相对有限，且老年患者在临床试验中的代表性不足，导致我们对衰老相关肿瘤机制的理解存在空白。尽管组织学、乳腺影像学、细胞及分子生物学分析已经揭示了人类和小鼠乳腺组织在衰老过程中发生的显著变化，但这些变化在乳腺肿瘤发生中的功能性作用仍未得到明确阐明【3-5】。这一领域的深入研究对于揭示肿瘤发生的潜在机制，并为乳腺癌的早期干预提供新的方向，具有重要意义。 为此，2024年10月3日，哈佛医学院Dana-Farber癌症研究所Kornelia Polyak团队（颜鹏泽博士为该研究的第一作者）在Cancer Cell在线发表题为Midkine as a driver of age-related changes and increase in mammary tumorigenesis的研究论文。研究系统揭示了中期因子（MDK，Midkine）在介导乳腺衰老及肿瘤发生中的重要作用，探讨了其潜在的机制与临床意义。 该研究首先通过单细胞多组学测序和组织学分析，对不同年龄的大鼠乳腺组织进行了详细分析，发现随着年龄增长，乳腺组织内的细胞组成和分子特征发生了显著变化。研究团队观察到，老年大鼠中上皮细胞出现异常增殖，并且出现一群具有癌变特征的管腔祖细胞（Aging-LP）。同时，乳腺组织中原始B细胞和T细胞的比例下降，这表明随着年龄的增长，乳腺微环境向更易致癌的状态转变。重点研究发现，Midkine在老年大鼠和人类的乳腺上皮细胞中显著上调，并且在年轻大鼠（1月龄）中进行为期一个月的Midkine处理后，其乳腺组织表现出类似于衰老大鼠（22月龄）的特征。具体来说，Midkine通过激活PI3K-AKT-SREBF1信号通路，导致了乳腺上皮细胞的异常增殖和Aging-LP的出现。这一发现为理解Midkine如何驱动衰老相关肿瘤提供了重要线索。 研究团队在实验中还利用了NMU（N-亚硝基-N-甲基脲）诱导大鼠乳腺肿瘤模型，该模型具有与人类雌激素受体阳性（ER+）乳腺癌高度相似的组织病理特征，并且保留了完整的免疫系统，适合研究肿瘤微环境及宿主-肿瘤相互作用，广泛用于乳腺癌机制研究和药物筛选【6】。基于该模型的实验结果表明，Midkine处理的年轻大鼠比对照组更容易形成肿瘤，且肿瘤生长速率更快。这一发现进一步证明了Midkine在肿瘤发生过程中的关键角色，提示其可能作为预防与治疗肿瘤的新靶点。 进一步的分析表明，健康个体的血浆中Midkine水平与年龄呈正相关，这表明Midkine可能作为一种新型衰老生物标志物。Midkine也在多种人类癌症类型中显著上调，包括乳腺癌。与正常乳腺组织相比，DCIS（导管内癌）和IBC（侵袭性乳腺癌）患者样本中的Midkine水平显著升高。此外，年轻HR+（激素受体阳性）乳腺癌患者中，MDK表达较高的患者其疾病特异性生存期明显缩短，这表明MDK可以作为HR+乳腺癌中的一个与年龄相关的预后标志物。在年轻健康女性中，正常乳腺组织中较高的MDK表达与更高的乳腺癌风险相关，暗示MDK也是一个与年龄相关的乳腺癌风险预测因子。 总体而言，该研究不仅揭示了Midkine在衰老及乳腺肿瘤发生中的重要作用，还为未来的临床研究提供了新的视角与可能性。研究成果为理解衰老相关肿瘤的发病机制和发展新的干预策略奠定了基础，具有重要的生物学和临床应用价值。 模式图（Credit: Cancer Cell） 参考文献 1. Peto, J. (2001). Cancer epidemiology in the last century and the next decade. Nature 411, 390-395. 10.1038/35077256. 2. Bidoli, E., Virdone, S., Hamdi-Cherif, M., Toffolutti, F., Taborelli, M., Panato, C., and Serraino, D. (2019). Worldwide Age at Onset of Female Breast Cancer: A 25-Year Population-Based Cancer Registry Study. Sci Rep 9, 14111. 10.1038/s41598-019-50680-5. 3. Gray, G.K., Li, C.M., Rosenbluth, J.M., Selfors, L.M., Girnius, N., Lin, J.R., Schackmann, R.C.J., Goh, W.L., Moore, K., Shapiro, H.K., et al. (2022). A human breast atlas integrating single-cell proteomics and transcriptomics. Dev Cell 57, 1400-1420.e1407. 10.1016/j.devcel.2022.05.003. 4. Reed, A.D., Pensa, S., Steif, A., Stenning, J., Kunz, D.J., Porter, L.J., Hua, K., He, P., Twigger, A.J., Siu, A.J.Q., et al. (2024). A single-cell atlas enables mapping of homeostatic cellular shifts in the adult human breast. Nat Genet 56, 652-662. 10.1038/s41588-024-01688-9. 5. Pelissier Vatter, F.A., Schapiro, D., Chang, H., Borowsky, A.D., Lee, J.K., Parvin, B., Stampfer, M.R., LaBarge, M.A., Bodenmiller, B., and Lorens, J.B. (2018). High-Dimensional Phenotyping Identifies Age-Emergent Cells in Human Mammary Epithelia. Cell Rep 23, 1205-1219. 10.1016/j.celrep.2018.03.114. 6. Gil Del Alcazar, C.R., Trinh, A., Aleckovic, M., Rojas Jimenez, E., Harper, N.W., Oliphant, M.U.J., Xie, S., Krop, E.D., Lulseged, B., Murphy, K.C., et al. (2022). Insights into Immune Escape During Tumor Evolution and Response to Immunotherapy Using a Rat Model of Breast Cancer. Cancer Immunol Res 10, 680-697. 10.1158/2326-6066.CIR-21-0804. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.ccell.2024.09.002 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