Dynamics of protein kinase CK2 signaling in prostate cancer pathogenesis

前列腺癌（PCa）是老年退伍军人群体面临的主要健康问题之一。 研究，以进一步推进疾病的病理生物学知识和受益PCa患者，这符合 退伍军人医疗使命。在这方面，我们的重点一直集中在界定 促生存和癌症成瘾蛋白激酶CK2在PCa病理生物学和治疗中的作用， 突破性的贡献。蛋白激酶CK2（以前称为酪蛋白激酶2或II）最初是 我们研究了与前列腺生物学有关的CK2，现在CK2被认为是前列腺的"主调节因子"之一。 在正常和恶性细胞中的不同功能。较高的相对CK2水平和活性对应于 在侵袭性PCa疾病中，CK2蛋白优先定位于PCa肿瘤的细胞核。串扰 雄激素受体（AR）、NF κ B B p65和CK 2之间的相互作用已被我们和其他人证实。抗CK2治疗 导致AR和NF κ B p65丢失，无论前列腺癌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;然而， 雄激素剥夺的发展与去势敏感性去势抵抗性前列腺癌（CRPC）的进展。 对下一代抗雄激素方法的应答（使用阿比特龙和/或Enzalutamide ± 化疗和最近的免疫疗法）也是暂时的， 因此，转移性CRPC（mCRPC）的死亡率仍然很高。因此，迫切需要 以确定维持药物反应和预防疾病进展的策略。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细胞表现出升高的CK2水平; (2)CK2蛋白水平在去势小鼠与睾丸完整小鼠的多个PCa异种移植肿瘤模型中更高;（3） CK2 α mRNA在前列腺癌患者术前血清中检测到， 阿比特龙治疗的PCa患者血清;（4）在肿瘤切除术时肿瘤中的高CK2蛋白水平与 （5）CK2的抑制杀死阿比特龙， Enzalutamide耐药PCa细胞，并与阿比特龙协同。这些令人兴奋的新观察促使 CK2的诱导以及随后对AR和NF κ B通路的影响促进治疗的假设 对当前AR靶向治疗的抗性。我们建议确定参与CK2的分子机制， 促进雄激素途径治疗抵抗，并确定CK2如何作为PCa的驱动因素发挥作用 疾病进展。具体目标1将检验CK2活性抑制将延迟或 预防前列腺癌进展或逆转对雄激素通路靶向的耐药性，并旨在检查 临床级抗CK2小分子抑制剂CX-4945对雄激素通路的影响及其机制 耐药性我们将采用模拟PCa进展和CRPC的小鼠异种移植物和PDX模型， status.具体目标2是检验雄激素应激下升高的CK2将改变蛋白质组学的假设。 与抑制细胞死亡途径相关的景观，并为PCa进展提供新的见解。这 目的将涉及确定增加的CK2水平对核蛋白质组学和磷酸蛋白质组学的影响， 雄激素应激下PCa细胞的组成，蛋白质组学变化和机制途径的验证， 异种移植肿瘤（包括PDX模型）和PCa患者组织，以及研究PCa患者组织中的分子生物学特性。 在这些条件下CK2水平增加的机制。我们的新方向在拟议中 调查将产生知识，为潜在的突破性翻译奠定基础， PCa患者的诊所。此外，他们将产生有关机制的重要数据，这些机制将解释CK2 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/磷酸蛋白质组学景观的特定影响而进展。

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.