IL-4 and androgen receptor signaling in prostate cancer

前列腺癌中的 IL-4 和雄激素受体信号传导

• 批准号: 7585196
• 负责人: Allen C Gao
• 金额: $ 21.31万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585196
• 关键词: Affect; Androgen Receptor; Androgens; Antiandrogen Therapy; Apoptosis; Apoptotic; Cancer Cell Growth; Cell Death; Cell Line; Cell Survival; Cells; Clinical Data; Complex; Data; Dependence; Development; Dominant-Negative Mutation; Genes; Genetic Transcription; Goals; Growth; Human; In Vitro; Interleukin-4; LNCaP; Ligands; Link; Malignant neoplasm of prostate; Mediating; NF-kappa B; Nuclear; PC3 cell line; Pathway interactions; Patients; Prostate; Prostate-Specific Antigen; Publishing; Receptor Activation; Receptor Signaling; Recurrence; Reporting; Research Personnel; Resistance; Role; Serum; Signal Pathway; Signal Transduction; Testing; androgen independent prostate cancer; base; cancer cell; deprivation; in vivo; inhibitor/antagonist; men; prevent; programs; promoter; tumorigenesis

DESCRIPTION (provided by applicant): Almost all patients with advanced prostate cancer respond initially to androgen deprivation and antiandrogen therapy. However, in virtually all patients, prostate cancer will recur due to growth of cancer cells that do not require androgens. While the exact mechanisms are not known, accumulating evidence indicates that abnormal (i.e., ligand-independent) activation of androgen receptor (AR) and development of apoptotic resistant cells contribute to prostate cancer androgen-independent growth. Our data demonstrates that interleukin-4 (IL-4) activates AR signaling in the presence of very low levels of androgen or in the absence of androgen. In addition, we have found that IL-4 protects androgen sensitive LNCaP human prostate cancer cells from apoptotic cell death initiated by androgen deprivation. IL-4 activates Akt, NF-kappaB and Stat6 in prostate cancer cells. NF-kappaB activation by IL-4 appears to occur by the Akt pathway. The activity of NF-kappaB and Stat6 is elevated in prostate cancer compared to normal prostate. These findings are important because the Akt->NF-kappaB signaling pathway has been demonstrated to promote tumorigenesis by inhibiting apoptosis. The hypothesis is that IL-4 induced cell signaling is a critical regulator of AR signaling and facilitates androgen-independent growth of prostate cancer. To test this hypothesis, 3 aims are proposed. 1. To determine the role of IL-4 on AR activation and androgen responsiveness of prostate cancer cells. Prostate cancer cell lines that express increased levels of IL-4 will be established. The effects of constitutive expression of IL-4 on androgen-mediated prostate cancer cell growth in vitro and in vivo and on the expression of androgen-inducible genes will be examined. 2. To determine the role of Akt->NF-kappaB and Stat6 signaling in IL-4 mediated AR activation and androgen responsiveness. Inhibitors and dominant negative mutants or forced expression of activated Stat6 and Akt->NF-kappaB will be used to determine the requirement of these signaling pathways in IL-4 mediated AR activation. 3. To determine whether Akt-> NF-kappaB signaling is required for IL-4 mediated survival of prostate cancer cells.

描述（由申请人提供）：几乎所有患有晚期前列腺癌的患者最初都对雄激素剥夺和抗雄激素治疗有反应。但是，在几乎所有患者中，由于不需要雄激素的癌细胞的生长，前列腺癌将复发。虽然确切的机制尚不清楚，但积累的证据表明，雄激素受体（AR）（AR）的异常（即配体独立于配体）激活以及凋亡抗性细胞的发展有助于前列腺癌雄激素独立的生长。我们的数据表明，白介素-4（IL-4）在存在非常低的雄激素或不存在雄激素的情况下激活AR信号传导。此外，我们发现IL-4保护雄激素敏感的LNCAP人前列腺癌细胞免受雄激素剥夺引发的凋亡细胞死亡。 IL-4在前列腺癌细胞中激活AKT，NF-kappab和STAT6。 IL-4的NF-kappab激活似乎是通过AKT途径发生的。与正常前列腺相比，前列腺癌中NF-kappab和STAT6的活性升高。这些发现很重要，因为已经证明AKT-> NF-kappab信号通路可以通过抑制凋亡来促进肿瘤发生。假设是IL-4诱导的细胞信号传导是AR信号传导的关键调节剂，并促进前列腺癌的雄激素独立生长。为了检验这一假设，提出了3个目标。 1。确定IL-4对前列腺癌细胞AR激活和雄激素反应性的作用。将建立表达IL-4水平升高的前列腺癌细胞系。 IL-4的本构表达对雄激素介导的前列腺癌细胞生长的体外和体内以及雄激素诱导基因的表达的影响。 2。确定Akt-> nf-kappab和STAT6信号在IL-4介导的AR激活和雄激素反应性中的作用。抑制剂和显性阴性突变体或激活的STAT6和Akt-> nF-kappab的强制表达将用于确定IL-4介导的AR激活中这些信号传导途径的需求。 3。确定IL-4介导的前列腺癌细胞存活是否需要Akt-> NF-kappab信号传导。

项目成果

Molecular mechanisms of castration-resistant prostate cancer progression.

• DOI: 10.2217/fon.09.117
• 发表时间: 2009-11
• 期刊: Future oncology (London, England)
• 作者: Dutt SS;Gao AC
• 通讯作者: Gao AC

Interleukin-6 regulates androgen synthesis in prostate cancer cells.

• DOI: 10.1158/1078-0432.ccr-09-0640
• 发表时间: 2009-08-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Chun JY;Nadiminty N;Dutt S;Lou W;Yang JC;Kung HJ;Evans CP;Gao AC
• 通讯作者: Gao AC

RhoGDIα suppresses growth and survival of prostate cancer cells.

• DOI: 10.1002/pros.21441
• 发表时间: 2012-03
• 期刊: PROSTATE
• 影响因子: 2.8
• 作者: Zhu, Yezi;Tummala, Ramakumar;Liu, Chengfei;Nadiminty, Nagalakshmi;Lou, Wei;Evans, Christopher P.;Zhou, Qinghua;Gao, Allen C.
• 通讯作者: Gao, Allen C.

Aberrant activation of the androgen receptor by NF-kappaB2/p52 in prostate cancer cells.

• DOI: 10.1158/0008-5472.can-09-3703
• 发表时间: 2010-04-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Nadiminty N;Lou W;Sun M;Chen J;Yue J;Kung HJ;Evans CP;Zhou Q;Gao AC
• 通讯作者: Gao AC

Sanguinarine suppresses prostate tumor growth and inhibits survivin expression.

• DOI: 10.1177/1947601910368849
• 发表时间: 2010-03
• 期刊: Genes & cancer
• 作者: Sun M;Lou W;Chun JY;Cho DS;Nadiminty N;Evans CP;Chen J;Yue J;Zhou Q;Gao AC
• 通讯作者: Gao AC