Acid Ceramidase in Prostate Cancer Biology and Therapeutics

前列腺癌生物学和治疗中的酸性神经酰胺酶

基本信息

批准号：
8381025
负责人：
James S Norris
金额：
$ 21.88万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8381025
关键词：
Adhesions Apoptosis Cancer Biology Cancer Cell Growth Cell Cycle Cell Cycle Regulation Cell Fate Control Cell Line Cells Ceramides Cessation of life Cisplatin Clinic Clinical Collagen Data Development Down-Regulation Doxorubicin Drug resistance Enzymes Equilibrium Etoposide Event Exhibits Genes Genetic Transcription Gleason Grade for Prostate Cancer Growth Homeostasis Human Immunohistochemistry In Vitro Intention Lead Lipids Malignant Neoplasms Malignant neoplasm of prostate Mediating Microarray Analysis Neoplasm Metastasis Oncogenic Outcome Paclitaxel Pathway interactions Patients Phenotype Play Prostate Cancer therapy Prostatic Neoplasms Proteins Proteomics Publishing Recurrence Regulation Resistance Role Sphingolipids Sphingosine Therapeutic Time Tissues Translating Tumor Biology Tumor Suppressor Proteins Tumor Tissue Up-Regulation Western Blotting Xenograft procedure angiogenesis cancer cell cancer therapy cell growth chemotherapy clinically relevant clinically significant deacylation galactosylgalactosylglucosylceramidase gemcitabine gene interaction improved in vivo inhibitor/antagonist insight migration neoplastic cell new therapeutic target novel outcome forecast response small molecule sphingosine 1-phosphate sphingosine kinase tumor

项目摘要

Acid ceramidase (AC) is a key enzyme in the sphingolipid rheostat which controls the relationship between ceramide (Cer) and sphingosine (Sph) sphingosine-1-phosphate (S1P) in the cell. Ceramide is associated with cell cycle control and apoptosis, and is thusly termed a tumor suppressor lipid. S1P promotes an antiapoptotic phenotype associated with improved angiogenesis, growth and metastasis. Thus, the balance of these two sphingolipids is very important in dictating cellular death or survival. Acid ceramidase is intimately involved in regulation of the pathway by deacylation of Cer forming Sph, the substrate of sphingosine kinase (SK1) which catalyses formation of S1P. Over-expression of SK1 has been shown to be oncogenic, making it by definition intimately involved in regulation of cell fate and/or development of cancer. In published studies, we have demonstrated that AC over-expression in prostate cancer (PCa) cells promotes cancer cell growth, migration, adhesion and mediates resistance to doxorubicin, taxol, etoposide, gemcitabine and cisplatin. This is therefore highly relevant to human cancer since >60% of Gleason grade 5-6 and 80% of Gleason grade 8-10 prostate cancers over-express AC. This leads to the long-term objective of this project which is to understand the consequences of AC up-regulation on progression and metastasis of prostate cancer (PCa) and determine how AC contributes to chemotherapy resistance. From a therapeutic view point, we believe that down-regulation of AC may play a role favoring pro-apoptosis by shifting the balance toward ceramide and away from S1P in tumors. We will examine this in three specific aims. The first aim will firmly establish that AC is over-expressing in primary PCa tissues compared to adjacent controls and to determine the clinical relevance of this observation. The second aim will be to determine the functional consequence of AC over-expression on PCa biology. The third specific aim will determine the role of AC in resistance to chemotherapy and if inhibition of AC promotes a therapeutic response in vivo. Taken together, we believe these studies will identify AC as a major prognosticator for therapeutic outcomes in PCa clinical therapy. This information will be used to develop therapeutic strategies to improve PCa therapy with the intention of translating this to the clinic.

酸性神经酰胺酶 (AC) 是鞘脂变阻器中的关键酶，它控制着细胞中的神经酰胺 (Cer) 和鞘氨醇 (Sph) 1-磷酸鞘氨醇 (S1P)。神经酰胺相关具有细胞周期控制和细胞凋亡的作用，因此被称为肿瘤抑制脂质。 S1P 促进抗细胞凋亡与改善血管生成、生长和转移相关的表型。因此，平衡这两种鞘脂对于决定细胞的死亡或存活非常重要。酸性神经酰胺酶与参与通过 Cer 脱酰化形成 Sph（鞘氨醇激酶的底物）的途径的调节 (SK1) 催化 S1P 的形成。 SK1 的过度表达已被证明具有致癌性，使得根据定义，它密切参与细胞命运的调节和/或癌症的发展。在已发表的研究中，我们证明了前列腺癌 (PCa) 细胞中 AC 过度表达促进癌细胞生长、迁移、粘附并介导对阿霉素、紫杉醇、依托泊苷、吉西他滨和顺铂。因此，这与人类癌症高度相关，因为格里森等级的 60% 以上 5-6 和 80% 的格里森 8-10 级前列腺癌过度表达 AC。这导致了长期目标该项目的目的是了解 AC 上调对进展和转移的影响前列腺癌 (PCa) 并确定 AC 如何导致化疗耐药。来自一个从治疗的角度来看，我们认为 AC 的下调可能通过以下方式发挥有利于促凋亡的作用：将肿瘤中的平衡转向神经酰胺，远离 S1P。我们将从三个具体方面来研究这个问题目标。第一个目标将坚定地确定，与其他组织相比，AC 在原发性 PCa 组织中过度表达。相邻对照并确定该观察结果的临床相关性。第二个目标是确定 AC 过度表达对 PCa 生物学的功能影响。第三个具体目标是确定 AC 在化疗耐药中的作用以及抑制 AC 是否会促进治疗体内反应。总而言之，我们相信这些研究将确定 AC 作为主要的预测因子 PCa 临床治疗的治疗结果。这些信息将用于制定治疗策略改善 PCa 治疗，旨在将其转化为临床。