E2F2 in eugenol-induced melanoma growth inhibition

E2F2 在丁子香酚诱导的黑色素瘤生长抑制中的作用

• 批准号: 7002619
• 负责人: Rita Ghosh
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-28 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002619
• 关键词: allyl compound; cancer prevention; cell growth regulation; drug screening /evaluation; flow cytometry; gel mobility shift assay; genetic regulation; growth inhibitors; melanoma; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplasm /cancer remission /regression; neoplastic growth; phenols; plant extracts; polymerase chain reaction; small interfering RNA; terminal nick end labeling; transcription factor; western blottings

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to develop mechanism-based combination approaches that can either prevent the progression of primary cutaneous melanoma to metastatic disease and/or cause regression of metastatic melanoma. Primary cutaneous melanoma is treatable. The metastatic form is fatal with a 10-year survival rate of less than 5% in people who have stage IV disease. We have identified eugenol as a potent inhibitor of melanoma tumors. Published data from our laboratory also shows that eugenol prevents the metastasis of tumors in B16 xenografts. In this proposal we want to examine the role of the transcription factor E2F2 which we have found to be downregulated by eugenol in its growth inhibitory activity. We hypothesize that overexpression of E2F2 deregulates cell cycle control in melanoma cells and that downregulation of E2F2 is essential for eugenol-induced cell cycle block and apoptosis induction independent of DNA damage-signaling pathways. Our specific aim to test this hypothesis is: to identify the role of E2F2 in deregulating cell cycle progression in melanoma cells and its involvement in eugenol induced growth inhibitory effects. Specifically we will determine (i) if the inhibition of E2F2 can prevent the continuous cycling of melanoma cells (ii) if E2F2 is a key player in eugenol-induced S-phase block and apoptosis induction and (iii) if the signal for eugenol-induced E2F2 downregulation is dependent upon DNA damage signaling. This pilot proposal will define the role of E2F2 in eugenol-induced growth inhibition, apoptosis induction and cell cycle block during the progression of melanoma cells, and identify the influence of E2F2 on the continuous cycling of melanoma cells. We will also determine how targeting E2F2 can affect functions of other E2F family members such as compensating for the absence of E2F2 as well as identify whether eugenol directly downregulates E2F2 or whether the effect is mediated via DNA damage. It is clear that multiple pathways are deregulated in cancer, it is only logical that a combination of various agents (chemical and or biological) that target different pathways be used to attack cancer cells. In this effort it is of utmost importance that the mechanism(s) of action of individual compounds be understood so that a rational combination of agents may be developed. This proposal addresses this very core of cancer chemoprevention that aims to reduce the national burden of high cost of treatment and loss of productive life.

描述(由申请人提供)：这项建议的长期目标是开发基于机制的组合方法，既可以防止原发皮肤黑色素瘤发展为转移性疾病，也可以导致转移性黑色素瘤的消退。原发性皮肤黑色素瘤是可以治疗的。这种转移形式是致命的，在患有IV期疾病的人中，10年存活率不到5%。我们已经确定丁香酚是一种有效的黑色素瘤抑制物。我们实验室公布的数据还表明，丁香酚可以预防B16移植瘤的转移。在这项建议中，我们想要研究转录因子E2F2的作用，我们已经发现丁香酚下调了E2F2在其生长抑制活性中的作用。我们假设，E2F2的过表达解除了黑色素瘤细胞的细胞周期控制，并且E2F2的下调对于丁香酚诱导的细胞周期阻断和不依赖于DNA损伤信号通路的细胞凋亡诱导是必不可少的。我们验证这一假说的具体目的是：确定E2F2在解除对黑色素瘤细胞周期进程的调控中的作用，以及它参与丁香酚诱导的生长抑制效应。具体地说，我们将确定：(I)抑制E2F2是否可以阻止黑色素瘤细胞的连续周期；(Ii)E2F2是否在丁香酚诱导的S期阻滞和细胞凋亡诱导中起关键作用；(Iii)丁香酚诱导的E2F2下调是否依赖于DNA损伤信号。这一试验性方案将确定E2F2在丁香酚诱导的黑色素瘤细胞生长抑制、细胞凋亡诱导和细胞周期阻断中的作用，并确定E2F2对黑色素瘤细胞连续周期的影响。我们还将确定靶向E2F2如何影响其他E2F家族成员的功能，如补偿E2F2的缺失，以及确定丁香酚是否直接下调E2F2，或者这种影响是否通过DNA损伤介导。很明显，在癌症中，多个途径被解除调控，使用针对不同途径的各种药物(化学和/或生物)的组合来攻击癌细胞是合乎逻辑的。在这项工作中，最重要的是了解单个化合物的作用机理(S)，以便开发出合理的药剂组合。该提案涉及癌症化学预防的这一核心问题，其目的是减轻国家因高昂的治疗费用和生产生命损失而造成的负担。