Dynamics of protein kinase CK2 signaling in prostate cancer pathogenesis

蛋白激酶 CK2 信号在前列腺癌发病机制中的动态

• 批准号: 10341109
• 负责人: Khalil Ahmed
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341109
• 关键词: Affect; Aging; Androgen Receptor; Androgens; Automobile Driving; Biology; Cancer Patient; Castration; Cell Death; Cell Nucleus; Cell Survival; Cell physiology; Clinic; Clinical; Clinical Trials; Data; Diagnosis; Disease; Disease Progression; Drug Targeting; Drug resistance; Drug resistance pathway; Exhibits; Growth; Health; Healthcare; Immunotherapy; Investigation; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Messenger RNA; Metastatic to; Mission; Modeling; Molecular; Mus; Neoplasm Metastasis; Normal Cell; Nuclear; Oral; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phosphotransferases; Play; Prostate; Prostatectomy; Protein Dynamics; Protein Kinase; Proteins; Proteome; Proteomics; Resistance; Resistance development; Role; Serum; Signal Transduction; Stress; Testing; Testis; Time; Tissues; Translating; Translations; Validation; Xenograft Model; Xenograft procedure; abiraterone; advanced disease; advanced prostate cancer; androgen deprivation therapy; androgenic; cancer cell; casein kinase II; castration resistant prostate cancer; cell growth; chemotherapy; deprivation; design; drug sensitivity; enzalutamide; experimental study; improved; inhibitor; insight; men; military veteran; mortality; next generation; novel; p65; patient derived xenograft model; phosphoproteomics; prevent; prostate cancer cell; prostate cancer prevention; prostate cancer progression; protein function; protein kinase inhibitor; response; small molecule; small molecule inhibitor; standard of care; success; targeted cancer therapy; targeted treatment; therapy resistant; treatment response; tumor; tumor xenograft; virtual

Prostate cancer (PCa) is one of the major health issues for the aging Veterans population warranting investigations to further advance knowledge of the disease pathobiology and benefit PCa patients, which accords with the VA Healthcare mission. In this context, our focus has been centered on delineating the functions of the pro-survival and cancer-addictive protein kinase CK2 in PCa pathobiology and therapy, resulting in significant ground-breaking contributions over time. Protein kinase CK2 (formerly casein kinase 2 or II) was originally studied by us in relation to prostate biology, and CK2 is now recognized as one of the “master regulators” of diverse functions in normal and malignant cells. Higher relative CK2 levels and activity correspond with aggressive PCa disease, and CK2 proteins localize preferentially to the nucleus in PCa tumors. Crosstalk between androgen receptor (AR), NFκB p65 and CK2 is demonstrated by us and others. Anti-CK2 treatments cause loss of AR and NFκB p65, with cell death ensuing regardless of the androgen and drug sensitivity of PCa cells. Currently, androgen deprivation therapy is the standard of care for many PCa patients; however, resistance to androgen deprivation develops with progression from castration-sensitive to castration-resistant PCa (CRPC). Response to next generation anti-androgenic approaches (Abiraterone and/or Enzalutamide used ± chemotherapy and more recently immunotherapy) is also temporary with development of resistance to these therapies so that the mortality rates from metastatic CRPC (mCRPC) remain high. Thus, there is critical need for identification of strategies to maintain drug response and prevent disease progression. Our new data show: (1) PCa cells grown under multiple conditions that exert androgen pathway stress exhibit elevated CK2 levels; (2) CK2 protein levels are higher in multiple PCa xenograft tumor models in castrated vs. testes-intact mice; (3) CK2α mRNA is detected in pre-prostatectomy PCa patient serum, and the levels are significantly increased in abiraterone-treated PCa patients serum; (4) High CK2 protein levels in tumors at prostatectomy correlate significantly with faster progression to metastatic disease; and (5) Inhibition of CK2 kills Abiraterone- and Enzalutamide-resistant PCa cells, and is synergistic with Abiraterone. These exciting novel observations prompt the hypothesis that induction of CK2 and the subsequent impact on AR and NFκB pathways promotes therapy resistance to current AR targeting therapies. We propose to determine molecular mechanisms involved in CK2 promotion of androgen pathway therapy resistance, and establish how CK2 functions as a driving factor for PCa disease progression. Specific aim 1 will test the hypothesis that suppression of CK2 activity will delay or prevent PCa progression or reverse resistance to androgen pathway targeting, and is designed to examine the effect and mechanism of the clinical grade anti-CK2 small molecule inhibitor CX-4945 on androgen pathway drug resistance. We will employ mouse xenograft and PDX models that mimic PCa progression and CRPC status. Specific aim 2 is to test the hypothesis that elevated CK2 under androgen stress will alter the proteomic landscape related to suppression of cell death pathways and provide new insights into PCa progression. This aim will involve determining the effects of increased CK2 levels on the nuclear proteomic and phospho-proteomic composition of PCa cells under androgen stress, validation of proteomic changes and mechanistic pathways in xenograft tumors (including PDX models) and PCa patient tissues, and investigation of the molecular mechanism(s) by which CK2 levels increase under these conditions. Our novel direction in the proposed investigation will generate knowledge that will set the stage for potential ground-breaking translation into the clinic for PCa patients. Further, they will generate vital data about mechanisms that will explain how CK2 influences drug resistance and PCa cell survival, and elucidate regulatory functions of CK2 in PCa disease progression through specific effects on the nuclear proteomic/phospho-proteomic landscape.

前列腺癌（PCA）是老年退伍军人人口警告的主要健康问题之一 调查以进一步提高知识的病理生物学知识，并使PCA患者受益 带有VA医疗保健任务。在这种情况下，我们的重点一直集中在描述的功能上 PCA病理生物学和治疗中的促卵巢蛋白激酶CK2的促卵巢和癌症蛋白激酶，导致显着 随着时间的推移，开创性的贡献。蛋白激酶CK2（以前是酪蛋白激酶2或II）最初是 由我们研究与前列腺生物学有关，CK2现在被公认为是 潜水在正常和恶性细胞中的功能。较高的相对CK2水平和活动与 侵略性PCA疾病和CK2蛋白更适合PCA肿瘤中的细胞核。相声 我们和其他人在雄激素受体（AR），NFκBp65和CK2之间进行了证明。抗CK2治疗 导致AR和NFκBp65的损失，无论PCA的雄激素和药物敏感性如何 细胞。目前，雄激素剥夺疗法是许多PCA患者的护理标准。但是，阻力 雄激素剥夺的发展，从cast割敏感到castration抗性PCA（CRPC）的发展。 对下一代抗雄激素方法的反应（阿比罗酮和/或恩扎拉胺使用± 化学疗法和最近的免疫疗法）也是暂时的，随着对这些的耐药性的发展 疗法使转移性CRPC（MCRPC）的死亡率保持较高。那是急需的 确定维持药物反应并防止疾病进展的策略。我们的新数据显示： （1）在多种条件下生长的PCA细胞施加雄激素途径应力暴露于CK2水平； （2）在cas骨与睾丸直立小鼠的多个PCA畸形肿瘤模型中，CK2蛋白水平较高； （3） CK2αmRNA在pca前PCA患者血清中检测到CK2αMRNA，并且水平在 Abiraterone治疗的PCA患者血清； （4）前列腺切除术肿瘤中的高CK2蛋白水平相关 在转移性疾病的进展中，显着地显着； （5）抑制CK2杀死阿比罗酮 - 和 耐恩扎拉酰胺耐药的PCA细胞，与阿比罗酮协同作用。这些令人兴奋的新颖观察提示 CK2诱导以及对AR和NFκB途径的后续影响的假设促进了治疗 对当前AR靶向疗法的抗性。我们建议确定涉及CK2的分子机制 促进雄激素途径耐药性，并确定CK2作为PCA的驱动因素的作用 疾病进展。具体目标1将检验以下假设：抑制CK2活性会延迟或 防止PCA进展或反向雄激素途径靶向靶向，并旨在检查 临床级抗CK2小分子抑制剂CX-4945对雄激素途径的效果和机制 耐药性。我们将采用模仿PCA进展和CRPC的鼠标Xenographic和PDX模型 地位。具体目的2是检验以下假设：雄激素应力下升高的CK2会改变蛋白质组学 与抑制细胞死亡通路有关的景观，并为PCA进展提供了新的见解。这 AIM将涉及确定CK2水平增加对核蛋白质组学和磷酸蛋白质组学的影响 PCA细胞在雄激素胁迫下的组成，蛋白质组学变化的验证和机械途径 异种移植肿瘤（包括PDX模型）和PCA患者组织，并研究了分子 在这些条件下CK2水平增加的机制。我们在拟议中的新颖方向 投资将产生知识，为潜在的开创性翻译奠定基础 PCA患者的诊所。此外，他们将生成有关机制的重要数据，这些数据将解释CK2的方式 影响耐药性和PCA细胞存活，并阐明CK2在PCA疾病中的调节功能 通过对核蛋白质组学/磷酸化 - 蛋白质组景观的特定影响的进展。