Akt/CREB signaling: Target for prostate cancer

Akt/CREB ​​信号传导：前列腺癌的靶点

• 批准号: 8196336
• 负责人: ADDANKI PRATAP KUMAR
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196336
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Adenocarcinoma; Age; Aging; Androgens; Animal Model; Animals; Apoptosis; Biochemical; Biological; Biological Assay; CREB1 gene; Cancer Etiology; Cancer Patient; Cell Cycle; Cell Line; Cell Survival; Cells; Cessation of life; Chemopreventive Agent; Clinical Trials; Clinical assessments; Control Groups; Coupled; Cyclin D1; DNA Binding; DU145; Data; Development; Diagnostic Neoplasm Staging; Diet; Disease; Effectiveness; Environment; Evaluation; Exposure to; Fire - disasters; Future; Goals; Growth; Health; Healthcare; Heterogeneity; Human; Immunoblotting; Immunohistochemistry; In Vitro; Induction of Apoptosis; Inflammation; Inhibition of Cell Proliferation; Intervention; LNCaP; Laboratories; Life Expectancy; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Lesion; Methodology; Military Personnel; Modality; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Nuclear; Oils; Operative Surgical Procedures; Palpable; Pathway interactions; Patients; Phosphotransferases; Play; Poison; Population; Prevention; Prostate; Prostatic Neoplasms; Proteins; Publishing; Research; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Smoke; Staging; Therapeutic; Time; Tissues; Transcriptional Activation; Transcriptional Regulation; Transfection; Transgenic Organisms; Tuberculosis; Tumor stage; Veterans; War; Western Blotting; androgen independent prostate cancer; base; cancer cell; clinically significant; cost effective; deprivation; design; gel mobility shift assay; high risk; hormone refractory prostate cancer; human FRAP1 protein; in vivo; innovation; insight; leukemia; men; mortality; novel; novel strategies; overexpression; p65; pre-clinical; preclinical evaluation; prevent; promoter; prostate carcinogenesis; public health relevance; research study; tumor; tumor progression

DESCRIPTION (provided by applicant): Project Summary Despite advances in surgical and therapeutic approaches, veterans have a 4-times higher risk for developing prostate cancer compared with non-veterans. Therefore novel strategies to prevent or delay development and progression of clinically significant disease in this population are critical for successful management of prostate cancer. The goal of this VA-Merit proposal is to develop a safe and effective strategy for management of clinically significant prostate cancer using a novel bark extract namely NexrutineR. This is based on strong published and preliminary unpublished studies from our laboratory demonstrating (i) NexrutineR intervention inhibits early stage tumor development in a preclinical animal model that develops prostate cancer akin to humans; (ii) NexrutineR treatment reduces Akt activation, transcriptional activity of CREB and NF:B and expression of antiapoptotic protein FLIP in prostate cancer cells and (iii) overexpression of myristoylated Akt protects prostate cancer cells from NexrutineR - induced growth inhibition. Preliminary results also show that reduction in the protein levels of pmTOR (2448) and pAkt (473) within 2h of NexrutineR; implicating a role for Akt/mTOR signaling in NexrutineR-induced biological activities. Despite such promising results, the precise role of mTORC2/Akt signaling and signaling pathways downstream of Akt, including CREB in NexrutineR-induced inhibition of cell proliferation/survival and induction of apoptosis remains to be established. Further it is not known whether NexrutineR is effective only in preventing early stage prostate tumors or it will be effective in other stages of prostate cancer. In addition, published studies from our laboratory and other investigators demonstrate a good correlation between expression of FLIP, CREB, Akt, NF:B and tumor grade in human prostate cancer patients. This data supports the concept that a substantial number of VA patients with high grade prostate cancer may benefit from strategies targeting FLIP, CREB, Akt, NF:B signaling or pathways that activate these molecules. To date no studies have examined the potential for combined targeting of these critical signaling pathways for prostate cancer management. We have designed experiments to fill these critical gaps using state-of-the-art methodologies including magnetic resonance imaging (MRI) for monitoring tumor development in animals, siRNA approaches, ChIP analysis in addition to standard molecular and biochemical approaches. Although multicomponent approach has been successfully applied in the treatment of diseases such as tuberculosis, AIDS and leukemia, such strategies have not been exploited fully for prostate cancer management. Therefore our approach targeting mTORC2/Akt/mTORC1 and Akt/NF:B- mediated signaling pathways simultaneously that play a critical role in prostate cancer progression while using a safe and cost-effective herbal supplement is novel and innovative. Results from these studies will likely provide mechanistic data and a detailed preclinical evaluation, setting the stage for the clinical assessment of NexrutineR against prostate cancer in VA patients. PUBLIC HEALTH RELEVANCE: Project Narrative: A critical health care issue for the aging Veteran population is metastatic hormone refractory prostate cancer which accounts for most of the prostate cancer associated fatality. Although not explored in detail, it has been suggested that Veterans are more susceptible due to extended exposure to various toxic chemicals and smoke from oil well fires during war. In addition with increasing life expectancy of the Veteran population, prostate cancer will continue to be a major health problem. Therefore developing new non toxic treatment modalities are critical for protecting current and future armed forces personnel. Considering these problems and the known heterogeneity of prostate cancer, simultaneously targeting multiple critical signaling pathways that play a critical/major role during prostate carcinogenesis will have tremendous advantage and impact in keeping morbidity and mortality at bay. In addition these data will provide key insights for better design of future clinical trials for Veterans population who has developed prostate cancer.

描述（由申请人提供）： 尽管手术和治疗方法取得了进展，但退伍军人患前列腺癌的风险是非退伍军人的4倍。因此，预防或延迟该人群中临床显著疾病的发展和进展的新策略对于成功管理前列腺癌至关重要。该VA-Merit提案的目标是开发一种安全有效的策略，用于使用新型树皮提取物（即NexrutineR）管理具有临床意义的前列腺癌。这是基于我们实验室强有力的已发表和初步未发表的研究，证明（i）NexrutineR干预可抑制临床前动物模型中早期肿瘤的发展，该模型发展为类似于人类的前列腺癌;（ii）NexrutineR治疗可降低前列腺癌细胞中Akt活化、CREB和NF：B的转录活性以及抗凋亡蛋白FLIP的表达;（iii）肉豆蔻酰化Akt的过表达可保护前列腺癌细胞免受NexrutineR诱导的生长抑制。初步结果还显示，在NexrutineR的2小时内，pmTOR（2448）和pAkt（473）的蛋白水平降低;暗示Akt/mTOR信号传导在NexrutineR诱导的生物活性中的作用。尽管有这些有希望的结果，但mTORC 2/Akt信号传导和Akt下游信号传导途径（包括CREB）在NexrutineR诱导的细胞增殖/存活抑制和细胞凋亡诱导中的确切作用仍有待确定。此外，尚不清楚NexrutineR是否仅在预防早期前列腺肿瘤方面有效，或者它是否在前列腺癌的其他阶段有效。此外，我们实验室和其他研究者发表的研究表明，在人前列腺癌患者中，FLIP、CREB、Akt、NF：B的表达与肿瘤分级之间具有良好的相关性。该数据支持以下概念：大量患有高级别前列腺癌的VA患者可能受益于靶向FLIP、CREB B、Akt、NF：B信号传导或激活这些分子的途径的策略。到目前为止，还没有研究检查联合靶向这些关键信号通路用于前列腺癌管理的潜力。我们已经设计了实验，以填补这些关键的差距，使用最先进的方法，包括磁共振成像（MRI）监测肿瘤在动物中的发展，siRNA的方法，ChIP分析，除了标准的分子和生化方法。虽然多组分方法已成功地应用于结核病、艾滋病和白血病等疾病的治疗，但这些策略尚未充分用于前列腺癌的治疗。因此，我们的方法同时靶向mTORC 2/Akt/mTORC 1和Akt/NF：B介导的信号通路，这些通路在前列腺癌进展中起关键作用，同时使用安全且具有成本效益的草药补充剂是新颖和创新的。这些研究的结果可能会提供机制数据和详细的临床前评价，为NexrutineR治疗VA患者前列腺癌的临床评估奠定基础。 公共卫生相关性： 项目叙述：老年退伍军人群体的一个关键卫生保健问题是转移性激素难治性前列腺癌，其占前列腺癌相关死亡率的大部分。虽然没有详细探讨，但有人认为退伍军人更容易受到战争期间各种有毒化学品和油井大火烟雾的影响。此外，随着退伍军人人口预期寿命的增加，前列腺癌将继续成为一个主要的健康问题。因此，开发新的无毒治疗方式对于保护当前和未来的武装部队人员至关重要。考虑到这些问题和前列腺癌的已知异质性，同时靶向在前列腺癌发生过程中发挥关键/主要作用的多个关键信号通路将在控制发病率和死亡率方面具有巨大的优势和影响。此外，这些数据将为更好地设计未来患有前列腺癌的退伍军人人群的临床试验提供关键见解。