Ceramide synthase as a therapy target in prostate cancer
神经酰胺合酶作为前列腺癌的治疗靶点
基本信息
- 批准号:7341119
- 负责人:
- 金额:$ 31.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-02-09 至 2009-12-31
- 项目状态:已结题
- 来源:
- 关键词:ATM geneATM wt AlleleAcetatesAddressAnimal ModelAnimalsAntisense OligonucleotidesApoptosisApoptoticCell DeathCell LineCellsCeramidesDataDevelopmentDisruptionDoseEnzymesGenerationsGoalsHumanInduction of ApoptosisIsoenzymesLNCaPLactonesLeadLocalizedMalignant neoplasm of prostateMediatingMethodsMitochondriaMolecular TargetNude MiceOligonucleotidesPC3 cell linePathway interactionsPatientsPhorbolPhorbol EstersPhorbolsPhosphotransferasesProstateProstatic NeoplasmsProtein IsoformsProtein Kinase CRadiationRadiation therapyRadiosensitizationReagentRelapseReportingResearchResidual stateResistanceRoleSignal TransductionSiteSphingolipidsStructure of base of prostateTestingTissuesTreatment ProtocolsWorkXenograft Modelataxia telangiectasia mutated proteinbasecancer cellcitrate carrierclinical applicationdihydroceramide desaturasein vivoirradiationneoplastic cellradiation resistanceresearch studyresistance mechanismresponsesmall moleculetumortumor growth
项目摘要
DESCRIPTION (provided by applicant): The goal of this project is to develop modulators of radiation response able to overcome radiation resistance in human prostate tumor cells. Although radiation is able of permanently eradicate localized human prostate tumors, nearly 30% of patients treated with potentially curative radiotherapy relapse at the sites of the irradiated tumor due to residual radiation-resistant clonogens. In this application we propose to explore the mechanisms of resistance to radiation-induced apoptosis for the highly resistant, well-characterized human prostate cancer cell lines-LNCaP and CRW22Rv 1, Our preliminary data Show that activation of protein kinase C (PKC) isoforms by the phorbol ester 12,O-tetradecanoyl phorbol-13-acetate, (TPA), induces a moderate apoptotic response in these tumor cells, and sensitizes them towards radiation, induced apoptosis. We also showed that this apoptotic response is mediated by the enzyme ceramide synthase (CS) and de novo synthesis of ceramide. CS activity was previously reported by us to be negatively regulated by the Ataxia Telangiectasia-Mutated (ATM) gene. Our preliminary studies related to this application showed that in LNCaP and CRW22Rvl cells, TPA reduces ATM levels. We observed a similar reduction in ATM protein levels and radiosensitization using a diacylgycerol (DAG)-lactone, HK654, or antisense oligonucleotides to ATM (AS-ATM-ODNs). In this project, we propose to define the involvement of PKCa and PKC5 in TPAinduced apoptosis via activation of the ATM-CS pathway. We will also study the mechanisms of CS involvement in mitochondrial apoptosis, ceramide generation within the mitochondria, and the interaction between ceramide, PKC6 and/or Bax. Finally, we propose to study the role of the ATM-CS pathway in vivo in LNCaP and CWR22Rvl tumors growing orthotopically in nude mice. We will study the response to TPA ( radiation in response to both single-dose radiation as well as to fractionated radiation and will correlate tumor growth in these animals with tissue readouts. The proposed Specific Aims are interactive and address new and heretofore unknown mechanisms of TPA(radiation-induced cell death in prostate cancer cells and prostate animal models. Our research plan presents a signaling-based approach, to investigate new I hypotheses, about mechanisms of radiation resistance, which could provide a basis for modulation of the l radiation response in resistant human prostate tumor clones, with potential for clinical applications in the radiation management of human prostate cancer.
描述(由申请人提供):该项目的目标是开发能够克服人类前列腺肿瘤细胞的辐射抗性的辐射响应调节剂。尽管放射能够永久根除局部人类前列腺肿瘤,但在接受潜在治愈性放射治疗的患者中,由于残留的抗放射克隆原,近 30% 的患者在受放射治疗的肿瘤部位会出现复发。在本申请中,我们打算探索高耐药性、特征良好的人前列腺癌细胞系 LNCaP 和 CRW22Rv 1 对辐射诱导细胞凋亡的抵抗机制,我们的初步数据表明,蛋白激酶 C (PKC) 亚型的激活通过佛波酯 12,O-十四酰基佛波醇-13-乙酸酯 (TPA) 可在这些肿瘤细胞中诱导适度的凋亡反应,并使它们敏感朝向辐射,诱导细胞凋亡。我们还表明,这种细胞凋亡反应是由神经酰胺合酶(CS)和神经酰胺从头合成介导的。我们之前报道过 CS 活性受到共济失调毛细血管扩张突变 (ATM) 基因的负调控。我们与该应用相关的初步研究表明,在 LNCaP 和 CRW22Rvl 细胞中,TPA 降低了 ATM 水平。我们观察到使用二酰基甘油 (DAG)-内酯、HK654 或 ATM 反义寡核苷酸 (AS-ATM-ODN) 时 ATM 蛋白水平和放射增敏作用有类似的降低。在这个项目中,我们建议通过激活 ATM-CS 途径来定义 PKCa 和 PKC5 在 TPA 诱导的细胞凋亡中的参与。我们还将研究 CS 参与线粒体凋亡、线粒体内神经酰胺生成以及神经酰胺、PKC6 和/或 Bax 之间相互作用的机制。最后,我们建议研究体内 ATM-CS 通路在裸鼠原位生长的 LNCaP 和 CWR22Rvl 肿瘤中的作用。 我们将研究对 TPA(单剂量辐射和分次辐射的辐射反应)的反应,并将这些动物的肿瘤生长与组织读数相关联。所提出的具体目标是互动的,并解决 TPA 的新的和迄今为止未知的机制(前列腺癌细胞和前列腺动物模型中辐射诱导的细胞死亡。我们的研究计划提出了一种基于信号传导的方法,以研究关于抗辐射机制的新假设,这可以为调节前列腺癌细胞中的辐射反应提供基础。耐药人类前列腺肿瘤克隆,具有在人类前列腺癌放射治疗中临床应用的潜力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ADRIANA HAIMOVITZ-FRIEDMAN其他文献
ADRIANA HAIMOVITZ-FRIEDMAN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ADRIANA HAIMOVITZ-FRIEDMAN', 18)}}的其他基金
Ceramide synthase as a therapy target in prostate cancer
神经酰胺合酶作为前列腺癌的治疗靶点
- 批准号:
6870063 - 财政年份:2005
- 资助金额:
$ 31.94万 - 项目类别:
Ceramide synthase as a therapy target in prostate cancer
神经酰胺合酶作为前列腺癌的治疗靶点
- 批准号:
7015015 - 财政年份:2005
- 资助金额:
$ 31.94万 - 项目类别:
Ceramide synthase as a therapy target in prostate cancer
神经酰胺合酶作为前列腺癌的治疗靶点
- 批准号:
7535569 - 财政年份:2005
- 资助金额:
$ 31.94万 - 项目类别:
Ceramide synthase as a therapy target in prostate cancer
神经酰胺合酶作为前列腺癌的治疗靶点
- 批准号:
7174684 - 财政年份:2005
- 资助金额:
$ 31.94万 - 项目类别:
相似海外基金
Mechanisms of mitochondrial damage in ataxia-telangiectasia
共济失调毛细血管扩张症线粒体损伤的机制
- 批准号:
9105821 - 财政年份:2015
- 资助金额:
$ 31.94万 - 项目类别:
Identification of Loci Modifying Atm Lymphomagenesis
Atm 淋巴瘤发生基因座的鉴定
- 批准号:
9109591 - 财政年份:2015
- 资助金额:
$ 31.94万 - 项目类别:
Lymphoma development in the elderly: Perturbed posttranscriptional regulation
老年人淋巴瘤的发展:转录后调节受到干扰
- 批准号:
9280607 - 财政年份:2015
- 资助金额:
$ 31.94万 - 项目类别:
Lymphoma development in the elderly: Perturbed posttranscriptional regulation
老年人淋巴瘤的发展:转录后调节受到干扰
- 批准号:
8922159 - 财政年份:2015
- 资助金额:
$ 31.94万 - 项目类别: