The Par-4/PKCz complex in prostate cancer
前列腺癌中的 Par-4/PKCz 复合物
基本信息
- 批准号:8318275
- 负责人:
- 金额:$ 38.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-03-12 至 2014-01-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAccountingAndrogensAntiandrogen TherapyApoptoticBenign Prostatic HypertrophyBindingBiological ModelsCell Culture TechniquesCell DeathCell LineCell ProliferationCellsComplementComplexCountryDevelopmentDiagnosisDiagnosticDominant-Negative MutationEventGene ExpressionGenerationsGoalsGrowthHumanIncidenceIntraepithelial NeoplasiaInvestigationKnowledgeLabelLaboratoriesMalignant NeoplasmsMalignant neoplasm of prostateMediatingMediator of activation proteinMicroarray AnalysisModelingMolecularMolecular ProfilingMolecular TargetMusMutant Strains MiceNeoplasmsPAWR genePTEN genePharmaceutical PreparationsPhenotypePlayProcessPropertyProstateProstate AdenocarcinomaProstate carcinomaProstatic NeoplasmsRegulationResistance developmentRoleSignal PathwaySignal TransductionSignaling MoleculeStagingTestingTissue MicroarrayTumor Suppressor ProteinsWorkcancer gene expressioncancer initiationcancer typecell transformationeffective therapyin vivoindexingmenmutantnovelnovel therapeutic interventionprostate cancer preventionprostate carcinogenesisresearch studytumortumor progressiontumorigenesis
项目摘要
Project Summary
Prostate cancer is the most common malignancy among men in western countries. Prostate tumors initially
respond well to androgen ablation or anti-androgen therapy, but eventually enter an androgen-independent
stage with no effective therapy. Clearly, new therapeutic approaches are needed, and this will require a better
understanding of the signaling events that control prostate tumorigenesis.
Our laboratory has identified a new tumor suppressor, Par-4, which has pro-apoptotic activity and plays
a role in human prostate tumorigenesis. Our preliminary results have demonstrated that Par-4 is lost in 60% of
human prostate tumors, and that it binds and inhibits PKC¿, consequently reducing NF-¿B and Akt activation,
and increasing cell death. Interestingly, tissue microarray analysis of human prostate carcinomas revealed a
correlation between PKC¿ expression and increased Ki67 labeling indexes. Moreover, cancer gene-expression
profiles comparing PKC¿ levels in different stages of human prostate neoplasias showed that PKC¿ expression
was strongly correlated with a high degree of tumor aggressiveness. Therefore, the Par-4/PKC¿ complex
appears to be a relevant candidate mediator of prostate tumorigenesis. In preliminary studies, we found that
Par-4-/- mice developed benign hyperplasia and prostate intraepithelial neoplasias (PIN) that could progress to
prostate adenocarcinomas when combined with PTEN heterozygous deletion. Therefore, Par-4 emerges as a
novel tumor suppressor through its ability to impinge on two critical signaling pathways, NF-¿B and Akt, likely
through PKC¿.
The long-term goal of the studies proposed here is to unravel the signaling cascades involved in prostate
cancer initiation and progression. This work will test the hypothesis that the loss of Par-4 in combination with
PTEN haploinsufficiency triggers invasive prostate adenocarcinoma, and will determine the cellular and
molecular signaling pathways that control that process. Advances in the understanding of these phenomena
may uncover new perspectives on prostate carcinogenesis, and provide novel targets for prostate cancer
prevention, diagnosis, and therapy. Therefore, in this proposal we will 1) test the hypothesis that Par-4
deficiency in combination with PTEN heterozygosity leads to the generation of invasive prostate cancer; and 2)
determine the Par-4-mediated cellular and molecular mechanisms that are involved in prostate cancer
progression in the context of PTEN haploinsufficiency. This work will increase our understanding of the
mechanisms involved in the regulation of prostate carcinogenesis, and in the long term will provide the
knowledge necessary for the development of novel, more specific, and thus less toxic, therapies for the
treatment of prostate cancer.
项目总结
项目成果
期刊论文数量(0)
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Maria Teresa Diaz Meco Conde其他文献
Maria Teresa Diaz Meco Conde的其他文献
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{{ truncateString('Maria Teresa Diaz Meco Conde', 18)}}的其他基金
Role of the CD44/Hyaluronan axis in mesenchymal prostate cancer
CD44/透明质酸轴在间充质前列腺癌中的作用
- 批准号:
10745413 - 财政年份:2023
- 资助金额:
$ 38.44万 - 项目类别:
Novel Pathways in the Control of Lineage Plasticity in Neuroendocrine Prostate Cancer
控制神经内分泌前列腺癌谱系可塑性的新途径
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9903086 - 财政年份:2020
- 资助金额:
$ 38.44万 - 项目类别:
Novel Pathways in the Control of Lineage Plasticity in Neuroendocrine Prostate Cancer
控制神经内分泌前列腺癌谱系可塑性的新途径
- 批准号:
10155455 - 财政年份:2020
- 资助金额:
$ 38.44万 - 项目类别:
Novel Pathways in the Control of Lineage Plasticity in Neuroendocrine Prostate Cancer
控制神经内分泌前列腺癌谱系可塑性的新途径
- 批准号:
10397076 - 财政年份:2020
- 资助金额:
$ 38.44万 - 项目类别:
Novel Pathways in the Control of Lineage Plasticity in Neuroendocrine Prostate Cancer
控制神经内分泌前列腺癌谱系可塑性的新途径
- 批准号:
10616482 - 财政年份:2020
- 资助金额:
$ 38.44万 - 项目类别:
Role of p62 in metabolic reprograming of the tumor stroma in prostate cancer
p62 在前列腺癌肿瘤基质代谢重编程中的作用
- 批准号:
10220897 - 财政年份:2017
- 资助金额:
$ 38.44万 - 项目类别:
Role of p62 in metabolic reprograming of the tumor stroma in prostate cancer
p62 在前列腺癌肿瘤基质代谢重编程中的作用
- 批准号:
10142675 - 财政年份:2017
- 资助金额:
$ 38.44万 - 项目类别:
Role of p62 in metabolic reprograming of the tumor stroma in prostate cancer
p62 在前列腺癌肿瘤基质代谢重编程中的作用
- 批准号:
9365189 - 财政年份:2017
- 资助金额:
$ 38.44万 - 项目类别:
The p62/MEKK3 complex in mTORC1 activation
mTORC1 激活中的 p62/MEKK3 复合物
- 批准号:
9042999 - 财政年份:2015
- 资助金额:
$ 38.44万 - 项目类别:
The Par-4/PKCz complex in prostate cancer
前列腺癌中的 Par-4/PKCz 复合物
- 批准号:
7651604 - 财政年份:2009
- 资助金额:
$ 38.44万 - 项目类别:
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