CXCL13: a mediator of prostate cancer progression

CXCL13:前列腺癌进展的介质

基本信息

  • 批准号:
    9256445
  • 负责人:
  • 金额:
    $ 35.61万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-04-01 至 2020-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer-related deaths among men in the US. A large body of evidence links protein kinase C epsilon (PKC) to cancer progression. PKC is markedly up-regulated in epithelial cancers, including prostate cancer, potentially reflecting its involvement in the etiology and progression o the disease. We found that prostate-specific PKC transgenic mice (PB-PKC) develop preneoplastic lesions (PINs), and remarkably, they develop invasive prostatic adenocarcinomas in a Pten haplodeficient background. Understanding the molecular basis of this cooperativity is highly relevant, as loss of the tumor suppressor Pten, a negative regulator of the PI3K pathway, is a common alteration of prostate cancer. We generated a number of cellular models recapitulating PKC overexpression and Pten loss, which display enhanced growth, motility, and invasiveness in vitro, and acquire tumorigenic potential in nude mice. Moreover, gene profiling and bioinformatics analysis revealed that PKC overexpressing/Pten depleted cells display a pattern of gene expression distinctive of human metastatic prostate cancer. We found that the "top hit" in this microarray analysis is the chemokine CXCL13. Notably, PKC cooperates with Pten loss to strongly induce CXCL13 mRNA levels and its release, and RNAi depletion of CXCL13 or its receptor (CXCR5) impairs the ability of PKC overexpressing/Pten-deficient cells to proliferate and migrate. Preliminary data also suggest that PKC and PI3K are downstream effectors of CXCR5, suggesting a positive amplification loop that may act as a vicious cycle. In Specific Aim 1, we will establish the relevance of the CXCL13:CXCR5 axis in prostate tumorigenesis using an inducible silencing approach. A potential contribution of stromal CXCL13 will be examined using immunocompetent mice and depletion of lymphocytes involved in CXCL13 production. In addition, knock-out CXCL13 and CXCR5 mice will be crossed with PB- PKC mice as an approach to assess the requirement of the CXCL13:CXCR5 axis in the development of prostate lesions and the activation of key mitogenic/survival pathways. In Specific Aim 2, we will examine the role of CXCL13:CXCR5 in metastasis using intraprostatic injections and also assess the role of this pathway in metastatic dissemination to bone. Mechanistic studies will be pursued to explore the potential relevance of Rac, a small G-protein, and its exchange factors (Rac-GEFs) in the motile/invasive phenotype driven by the PKC-PI3K-CXCL13-CXCR5 pathway. In Specific Aim 3, we will focus on the mechanisms involved in CXCL13 induction by PKC and PI3K, specifically dissecting the roles of Akt, Erk, Stat3, NF-B and specific p110 PI3Ks in controlling CXCL13 production. We will also investigate PKC as a potential CXCR5 downstream effector. Lastly, in Specific Aim 4 we will establish the relevance of the PKC/Pten-CXCL13 association in human prostate tumors using a large collection of prostate cancer specimens, and assess correlations with disease progression and recurrence. In addition to the mechanistic implications, the proposed studies may have major prognostic and therapeutic impact for personalized prostate cancer treatment.


项目成果

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科研奖励数量(0)
会议论文数量(0)
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MARCELO G. KAZANIETZ其他文献

MARCELO G. KAZANIETZ的其他文献

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{{ truncateString('MARCELO G. KAZANIETZ', 18)}}的其他基金

Protein kinase C signaling in prostate cancer health disparities
前列腺癌健康差异中的蛋白激酶 C 信号传导
  • 批准号:
    10744533
  • 财政年份:
    2023
  • 资助金额:
    $ 35.61万
  • 项目类别:
Effectors of protein kinase C-mediated tumor progression
蛋白激酶 C 介导的肿瘤进展的效应器
  • 批准号:
    10543367
  • 财政年份:
    2022
  • 资助金额:
    $ 35.61万
  • 项目类别:
Rac guanine nucleotide exchange factors in lung cancer
肺癌中的 Rac 鸟嘌呤核苷酸交换因子
  • 批准号:
    10522390
  • 财政年份:
    2022
  • 资助金额:
    $ 35.61万
  • 项目类别:
Rac guanine nucleotide exchange factors in lung cancer
肺癌中的 Rac 鸟嘌呤核苷酸交换因子
  • 批准号:
    10674846
  • 财政年份:
    2022
  • 资助金额:
    $ 35.61万
  • 项目类别:
Effectors of protein kinase C-mediated tumor progression
蛋白激酶 C 介导的肿瘤进展的效应器
  • 批准号:
    9198206
  • 财政年份:
    2016
  • 资助金额:
    $ 35.61万
  • 项目类别:
Effectors of protein kinase C-mediated tumor progression
蛋白激酶 C 介导的肿瘤进展的效应器
  • 批准号:
    9042748
  • 财政年份:
    2016
  • 资助金额:
    $ 35.61万
  • 项目类别:
Protein kinase C and lung carcinogenesis
蛋白激酶C与肺癌发生
  • 批准号:
    9126982
  • 财政年份:
    2015
  • 资助金额:
    $ 35.61万
  • 项目类别:
ErbB receptor signaling via small G-proteins in breast cancer
乳腺癌中通过小 G 蛋白进行的 ErbB 受体信号传导
  • 批准号:
    8468659
  • 财政年份:
    2010
  • 资助金额:
    $ 35.61万
  • 项目类别:
ErbB receptor signaling via small G-proteins in breast cancer
乳腺癌中通过小 G 蛋白进行的 ErbB 受体信号传导
  • 批准号:
    8607903
  • 财政年份:
    2010
  • 资助金额:
    $ 35.61万
  • 项目类别:
ErbB receptor signaling via small G-proteins in breast cancer
乳腺癌中通过小 G 蛋白进行的 ErbB 受体信号传导
  • 批准号:
    8062243
  • 财政年份:
    2010
  • 资助金额:
    $ 35.61万
  • 项目类别:

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口服抗肿瘤药物的获取延迟
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