Dynamics of protein kinase CK2 signaling in prostate cancer pathogenesis

前列腺癌(PCa)是老年退伍军人面临的主要健康问题之一 进一步提高对疾病病理生物学的认识，使前列腺癌患者受益，这符合 与退伍军人管理局的医疗保健任务。在这方面，我们的重点一直集中在界定 在前列腺癌的病理生物学和治疗中，促生存和癌症成瘾蛋白激酶CK2，导致显著的 随着时间的推移，做出了开创性的贡献。蛋白激酶CK2(以前的酪蛋白激酶2或II)最初是 CK2是我们研究的与前列腺生物学有关的基因，现在被公认为是 在正常和恶性细胞中具有不同的功能。较高的相对CK2水平和活性对应于 侵袭性前列腺癌和CK2蛋白在前列腺癌中优先定位于细胞核。串扰 雄激素受体(AR)、核因子κB p65和CK2之间的关系已由我们和其他人证实。抗CK2治疗 导致AR和NFκB p65的丢失，细胞死亡与PCa的雄激素和药物敏感性无关 细胞。目前，雄激素剥夺治疗是许多前列腺癌患者的标准护理；然而，抵抗 雄激素缺乏伴随着去势敏感到去势抵抗的前列腺癌(CRPC)的发展。 对下一代抗雄激素药物的反应(阿比拉酮和/或恩扎鲁胺使用± 化疗和最近的免疫治疗)也是暂时的，对这些药物产生抗药性 治疗使转移性CRPC(MCRPC)的死亡率居高不下。因此，迫切需要 用于确定维持药物反应和防止疾病进展的战略。我们的新数据显示： (1)在施加雄激素途径应激的多种条件下生长的PCa细胞CK2水平升高； (2)在去势小鼠和睾丸完整小鼠的多个PCA移植瘤模型中，CK2蛋白水平较高； 前列腺癌患者手术前血清中检测到CK2α基因，且在前列腺癌患者血清中表达水平显著升高。 阿比特龙治疗前列腺癌患者的血清；(4)前列腺术中肿瘤中高水平的CK2蛋白与 显著地，更快地进展为转移性疾病；以及(5)抑制CK2可杀死阿比拉特隆-和 对苯扎鲁胺耐药的PCa细胞，与阿比拉特龙有协同作用。这些令人兴奋的新奇观察促使 CK2的诱导以及随后对AR和NFκB通路的影响促进治疗的假说 抵抗目前的AR靶向治疗。我们建议确定与CK2相关的分子机制 促进雄激素途径治疗耐药性，并确定CK2如何作为PCa的驱动因素 疾病的发展。特定目标1将检验抑制CK2活性将延迟或 防止前列腺癌进展或逆转对雄激素途径靶向的耐药性，旨在检查 临床级抗CK2小分子抑制剂CX-4945对雄激素途径的影响及其机制 抗药性。我们将使用小鼠异种移植和PDX模型来模拟PCA进展和CRPC 状态。具体目标2是验证在雄激素应激下升高的CK2将改变蛋白质组的假设 此外，我们还研究了与抑制细胞死亡途径相关的新图景，并提供了对PCA进展的新见解。这 目的将包括确定增加的CK2水平对核蛋白质组和磷酸蛋白质组的影响 雄激素应激下前列腺癌细胞的组成、蛋白质组学变化及其机制的验证 异种移植瘤(包括PDX模型)和PCa患者组织及其分子研究 在此条件下CK2水平升高的机制(S)。我们的小说方向在提出 调查将产生知识，为潜在的开创性翻译奠定基础 为前列腺癌患者提供门诊服务。此外，它们还将产生有关机制的重要数据，这些数据将解释CK2如何 CK2对PCa耐药和细胞存活的影响及其调控功能 通过对核蛋白质组/磷酸蛋白质组格局的特定影响而取得的进展。

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.