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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 脂肪酸代谢改变是癌症，尤其是前列腺癌的常见特征。 在肿瘤细胞中，大多数脂肪酸都是通过脂肪酸合酶（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 表达几乎是无法检测的。在前列腺肿瘤中，尽管环境很高 脂肪酸，FASN充分表达。我们的小组和其他人表明前列​​腺 过表达FASN的肿瘤表现出侵略性的生物学行为。抑制FASN通过 siRNA或化学抑制剂会导致肿瘤凋亡。 《抑制剂法》损害了其中之一 FASN的七个催化部位，停止了其最丰富的产品的生产， 棕榈酸酯。重要的是，挽救了抑制剂的细胞抑制和凋亡作用 当将棕榈酸盐添加到细胞中时。 脂肪酰化，即通过添加脂肪酸修饰蛋白质，是 真核细胞。具体而言，棕榈酰化是长链的翻译后添加 脂肪酸通过硫酯连接到半胱氨酸残留物。棕榈酰化是一个可逆的过程， 它允许快速调节蛋白质，类似于磷酸化。关键信号传导 已知参与癌症的蛋白质是棕榈酰基化的，例如RAS，SRC家族 成员（即p59fyn或p56lck）和Wnt。棕榈酸盐的添加是细胞的信号 膜定位，也被利用以调节突触，跨膜蛋白 和信号肽。 由于FASN抑制作用（如细胞凋亡或体内生长停滞）的影响可能部分是 由棕榈酸盐营救，我们建议癌细胞可能依靠棕榈酸酯代谢 保持其恶性表型。