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）：该提案的长期目标是开发基于机制的组合方法，可以防止原发性皮肤黑色素瘤进展为转移性疾病和/或引起转移性黑色素瘤消退。原发性皮肤黑色素瘤是可以治疗的。转移性癌症是致命的，IV 期疾病患者的 10 年生存率低于 5%。我们已经确定丁子香酚是黑色素瘤的有效抑制剂。我们实验室公布的数据还表明，丁子香酚可以预防 B16 异种移植物中的肿瘤转移。在本提案中，我们想要研究转录因子 E2F2 的作用，我们发现该因子在其生长抑制活性中被丁子香酚下调。我们假设 E2F2 的过度表达会解除黑色素瘤细胞中细胞周期控制的调节，并且 E2F2 的下调对于丁子香酚诱导的细胞周期阻滞和细胞凋亡诱导至关重要，而与 DNA 损伤信号通路无关。我们检验这一假设的具体目的是：确定 E2F2 在解除黑色素瘤细胞细胞周期进程中的作用及其与丁子香酚诱导的生长抑制作用的关系。具体来说，我们将确定（i）E2F2的抑制是否可以阻止黑色素瘤细胞的连续循环（ii）E2F2是否是丁子香酚诱导的S期阻滞和细胞凋亡诱导的关键参与者，以及（iii）丁子香酚的信号是否-诱导的 E2F2 下调依赖于 DNA 损伤信号传导。该试点提案将明确E2F2在黑色素瘤细胞进展过程中丁子香酚诱导的生长抑制、细胞凋亡诱导和细胞周期阻断中的作用，并确定E2F2对黑色素瘤细胞持续循环的影响。我们还将确定靶向 E2F2 如何影响其他 E2F 家族成员的功能，例如补偿 E2F2 的缺失，以及确定丁子香酚是否直接下调 E2F2 或该效应是否通过 DNA 损伤介导。很明显，癌症中多种途径被解除管制，使用针对不同途径的各种药剂（化学和/或生物）组合来攻击癌细胞是合乎逻辑的。在这项工作中，最重要的是了解各个化合物的作用机制，以便开发合理的药物组合。该提案解决了癌症化学预防的核心问题，旨在减轻高额治疗费用和生产力损失带来的国家负担。