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）是老年退伍军人的主要健康问题之一