An androgen-regulated cytokine network controls prostate apoptosis

雄激素调节的细胞因子网络控制前列腺细胞凋亡

• 批准号: 8735868
• 负责人: John J. Krolewski
• 金额: $ 28.97万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735868
• 关键词: Accounting; Adverse effects; Affect; Androgen Receptor; Androgens; Animals; Apoptosis; Apoptosis Inhibitor; Apoptotic; Castration; Cause of Death; Cell Line; Cessation of life; Clinical; Complex; Cytokine Network Pathway; Cytokine Signaling; Data; Detection; Development; Diagnosis; Differentiation and Growth; Disease; Disease Progression; Disseminated Malignant Neoplasm; Down-Regulation; Drug Targeting; Epigenetic Process; Epithelial; Epithelium; Genes; Genetic; Gland; Goals; Homologous Gene; Human; IGFBP3 gene; Image; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor Binding Protein 1; Knock-out; Knockout Mice; Localized Malignant Neoplasm; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medical; Messenger RNA; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Target; Mus; NF-kappa B; Neoplasm Metastasis; Operative Surgical Procedures; PTEN gene; Pathway interactions; Patients; Physiological; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Protocols documentation; Radiation; Receptor Signaling; Resistance; Rodent; Rodent Model; Role; Signal Pathway; Signal Transduction; Structure; Technology; Testing; Transforming Growth Factors; Tumor Necrosis Factor-alpha; Visceral; Withdrawal; arm; cancer surgery; cancer therapy; caspase-8; castration resistant prostate cancer; cytokine; deprivation; improved; in vivo; inhibitor/antagonist; innovation; men; mouse model; neoplastic; neoplastic cell; novel; paracrine; prostate cancer model; research study; response; small hairpin RNA; therapy design; therapy resistant; tumorigenic

DESCRIPTION (provided by applicant): The diagnosis and treatment of prostate cancer (PrCa) is a complex clinical problem that affects millions of men each year in the US, producing >200,000 new diagnoses and >27,000 deaths. Most PrCa is localized and slow growing; a smaller fraction metastasizes and causes death. Since prostate cancer derives from androgen dependent epithelium, some cases of localized PrCa and most cases of metastatic PrCa are treated via androgen deprivation therapy (ADT). ADT is a more specific therapy than surgery or radiation, inducing apoptosis in both localized and dispersed prostate epithelial tumor cells, rather than ablating the entire gland and causing damage to surrounding structures. However, androgens have systemic effects beyond regulating the growth and differentiation of prostate epithelium and ADT therefore produces considerable side-effects. Moreover, ADT frequently fails. The development of novel, targeted therapies that trigger PrCa apoptosis in a selective manner offers the possibility of reduced side-effects and improved control of disease progression. Our overall goal is to elucidate the mechanism of prostate apoptosis in response to androgen withdrawal, to eventually design therapies that selectively mimic the apoptotic effects of ADT. To achieve this goal, we have investigated androgen withdrawal induced apoptosis (AWIA) in normal rodents and model prostate cell lines. Recently, we developed a novel magnetic resonance imaging (CHESS-MRI) protocol to quantitate prostate regression and found that tumor necrosis factor (TNF) signaling is required, but not sufficient, for AWIA. Previously, we showed that FLIP, an inactive homologue of caspase-8 that inhibits TNF signaling, decreases following androgen withdrawal. The expression of both FLIP and TNF are androgen regulated. Two other cytokine signaling pathways (triggered by transforming growth factor-b (TGFb) and insulin-like growth factor 1 (IGF1)) have also been implicated in AWIA, and the corresponding genes are also androgen regulated. We will test the following central hypothesis: androgen withdrawal regulates a network of paracrine-acting cytokines (TNF, TGFb, IGF1, IGFBP3) and thereby reduces the expression of the intracellular apoptosis inhibitor FLIP. The net effect is to trigger the apoptotic arm of the TNF signaling pathway. The experimental plan utilizes rodent AWIA models and a prostate-specific PTEN-deficient mouse model resembling human prostate cancer, in conjunction with CHESS-MRI to image both normal and tumorous prostates. Aim 1 determines the role of TNF, TGFb and IGFBP3 in ADT-induced prostate apoptosis and whether these same cytokines cooperate to induce apoptosis in normal and tumorigenic prostates. Aim 2 investigates the role of TGFb and NF-kB cross-talk in mediating androgen deprivation induced down-regulation of FLIP. Finally, Aim 3 tests the functional role of FLIP, determining if FLIP down-regulation can cooperate with pro- apoptotic cytokines to induce apoptosis and regression of normal prostate and PrCa in a murine model.

描述(申请人提供)：前列腺癌(PrCa)的诊断和治疗是一个复杂的临床问题，每年在美国影响数百万男性，产生20万例新诊断和2.7万例死亡。大多数PrCa是局部性的，生长缓慢；一小部分转移并导致死亡。由于前列腺癌起源于雄激素依赖的上皮细胞，部分局限性PrCa和大多数转移性PrCa可通过雄激素剥夺疗法(ADT)进行治疗。ADT是一种比手术或放射治疗更特异的治疗方法，它诱导局部和分散的前列腺上皮肿瘤细胞凋亡，而不是切除整个腺体并对周围结构造成损害。然而，雄激素除了调节前列腺上皮的生长和分化外，还具有全身作用，因此ADT会产生相当大的副作用。此外，ADT经常失败。以选择性方式触发PrCa细胞凋亡的新型靶向疗法的发展提供了减少副作用和改善对疾病进展的控制的可能性。我们的总体目标是阐明雄激素停用后前列腺细胞凋亡的机制，最终设计选择性地模拟ADT的凋亡效应的治疗方法。为了实现这一目标，我们研究了雄激素停药诱导正常啮齿动物和模型前列腺细胞株的凋亡(AWIA)。最近，我们开发了一种新的磁共振成像(CHESS-MRI)方案来量化前列腺退行性变，发现肿瘤坏死因子(TNF)信号是AWIA所必需的，但不是充分的。此前，我们证明了flip，一种抑制肿瘤坏死因子信号的caspase-8的非活性同系物，在雄激素停药后减少。FLIP和肿瘤坏死因子的表达均受雄激素调控。另外两个细胞因子信号通路(由转化生长因子-b(TGFb)和胰岛素样生长因子1(IGF1)触发)也与AWIA有关，相应的基因也受雄激素调节。我们将检验以下中心假设：雄激素停药调节旁分泌作用细胞因子(TNF、TGFb、IGF1、IGFBP3)的网络，从而减少细胞内凋亡抑制因子FLIP的表达。最终的作用是触发肿瘤坏死因子信号通路的凋亡臂。该实验计划利用啮齿动物AWIA模型和类似于人类前列腺癌的前列腺特异性PTEN缺陷小鼠模型，结合CHESS-MRI对正常和肿瘤前列腺进行成像。目的1研究肿瘤坏死因子、肿瘤生长因子b和胰岛素样生长因子3在腺苷类药物ADT诱导的前列腺细胞凋亡中的作用，以及这些细胞因子是否协同作用诱导正常和癌变的前列腺细胞凋亡。目的2研究转化生长因子b和核因子-kB的相互作用在雄激素剥夺诱导的翻转基因下调中的作用。最后，Aim 3测试了FliP的功能作用，确定FliP下调是否可以与促凋亡细胞因子协同作用，在小鼠模型中诱导正常前列腺和PrCa的凋亡和消退。