PALMITOYLATION SIGNATURE IN PROSTATE CANCER CELL LINES

前列腺癌细胞系中的棕榈酰化特征

• 批准号: 8171371
• 负责人: Massimo Loda
• 金额: $ 0.71万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171371
• 关键词: Apoptosis; Apoptotic; Behavior; Biological; Catalytic Domain; Cells; Cellular Membrane; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Cysteine; Cytostatics; Diet; Eukaryotic Cell; Family member; Fatty Acids; Fatty-acid synthase; Funding; Grant; Growth; Institution; Integral Membrane Protein; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolism; Normal tissue morphology; PC3 cell line; Palmitates; Peptide Signal Sequences; Phosphorylation; Post-Translational Protein Processing; Process; Production; Prostatic Neoplasms; Proteins; Regulation; Research; Research Personnel; Resources; Signal Transduction; Signaling Protein; Small Interfering RNA; Source; Synapses; United States National Institutes of Health; cancer cell; fatty acid metabolism; fatty acylation; in vivo; inhibitor/antagonist; long chain fatty acid; malignant phenotype; neoplastic cell; overexpression; palmitoylation; thioester; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Altered fatty acid metabolism is a common feature of cancers, especially prostate cancer. In tumor cells, most fatty acids are synthesized de novo by fatty acid synthase (FASN), whereas in normal tissue, most of the fatty acids are supplied through the diet and FASN expression is almost undetectable. In prostate tumors, despite the high levels of ambient fatty acids, FASN is abundantly expressed. Our group and others showed that prostate tumors overexpressing-FASN display aggressive biological behavior. Inhibition of FASN via siRNA or chemical inhibitors, results in tumor apoptosis. The inhibitors act impairing one of the seven catalytic site of FASN, halting the production of its most abundant product, palmitate. Importantly, the cytostatic and apoptotic effects of the inhibitors are rescued when palmitate is added to the cells. Fatty acylation, i.e. protein modification by addition of fatty acids, is a common feature of eukaryotic cells. Specifically, palmitoylation is the posttranslational addition of long chain fatty acid to a cysteine residue via thioester linkage. Palmitoylation is a reversible process, and it allows for rapid regulation of protein, similar to phosphorylation. Critical signaling proteins involved in cancer are known to be palmitoylated such as Ras, Src family members (i.e. p59fyn or p56lck) and Wnt. Addition of palmitate is a signal for cellular membrane localization and is also exploited to regulate synapses, transmembrane proteins and signaling peptides. Since the effects of FASN inhibition like apoptosis or in vivo growth arrest, can be partially rescued by palmitate we proposed that cancer cells might rely on palmitate metabolism to maintain their malignant phenotype.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 脂肪酸代谢异常是癌症的共同特征，尤其是前列腺癌。 在肿瘤细胞中，大多数脂肪酸是由脂肪酸合成酶(FASN)从头合成的， 而在正常组织中，大多数脂肪酸是通过饮食和FASN提供的 表情几乎检测不到。在前列腺癌中，尽管环境中有很高的水平 脂肪酸、FASN大量表达。我们的团队和其他人表明，前列腺癌 肿瘤过度表达-FASN表现出侵袭性的生物学行为。FASN的抑制途径 SiRNA或化学抑制剂，导致肿瘤细胞凋亡。这些抑制剂的作用是损害以下一种 FASN的七个催化部位，停止了其最丰富产品的生产， 棕榈酸。重要的是，抑制物的细胞抑制和细胞凋亡作用被挽救了。 当细胞中加入棕榈酸酯时。 脂肪酰化，即通过添加脂肪酸对蛋白质进行修饰，是 真核细胞。具体地说，棕榈酰化是长链的翻译后加成 通过硫代酯键将脂肪酸转化为半胱氨酸残基。棕榈酰化是一个可逆的过程， 它允许蛋白质的快速调节，类似于磷酸化。关键信令 已知与癌症有关的蛋白质是棕榈酰化的，如Ras，Src家族 成员(即p59fyn或p56lck)和WNT。添加棕榈酸酯是细胞的信号 膜定位，也被用来调节突触、跨膜蛋白 和信号肽。 由于FASN的抑制作用，如细胞凋亡或体内生长停滞，可以部分地 在棕榈酸酯的拯救下，我们提出癌细胞可能依赖棕榈酸酯代谢来 维持他们的恶性表型。