A novel sulforaphane cancer preventionmechanism

一种新型萝卜硫素癌症预防机制

• 批准号: 10335161
• 负责人: Richard L. Eckert
• 金额: $ 36.3万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335161
• 关键词: Biological; Blood Vessels; Cell Survival; Cells; Dangerousness; Data; Development; Diet; Disseminated Malignant Neoplasm; Excision; Frequencies; GTP Binding; Goals; Human; Knock-out; Maintenance; Malignant Neoplasms; Mediator of activation protein; Modification; Molecular Conformation; Monitor; Morphology; Operative Surgical Procedures; Prevention approach; Process; Progressive Disease; Proteins; Recurrence; Regulation; Resistance; Role; Signal Transduction; Skin Cancer; Squamous cell carcinoma; Structure; Sulforaphane; System; Testing; Tumor Stem Cells; cancer cell; cancer prevention; cancer stem cell; carcinogenicity; conventional therapy; cruciferous vegetable; design; interest; knock-down; migration; novel; overexpression; prevent; protein biomarkers; response; self-renewal; stem cell biomarkers; stem cell survival; transglutaminase 2; tumor; tumor growth

Epidermal squamous cell carcinoma (SCC) is among the most frequent of cancers. It is treated by surgical excision, but the recurrence and metastatic rates approach 10%. Our scientific premise is that human epidermal cancer stem (ECS) cells are formed early in skin cancer and these cells are important cancer prevention targets. An important goal in this context is identifying and inhibiting activity of key proteins that are elevated and essential for ECS cell survival. Of particular interest, we show that tissue transglutaminase (TG2), an emerging cancer stem cell survival regulator, is highly elevated in ECS cells as compared to non- stem cancer cells. Of further importance, TG2 knockdown or treatment with sulforaphane (SFN), a promising diet-derived cancer prevention agent, reduces TG2 activity which is associated with reduced ECS cell survival and additional new studies indicate that TG2-knockout markedly reduces ECS cell tumor formation. We also provide new data suggesting that SFN covalently modifies TG2 to shifts its structure to an open inactivate conformation. These novel findings suggest that SFN treatment converts TG2 from a closed (GTP binding, signaling) pro-ECS cell survival form to an open inactive conformation. Our goal is to characterize this unique regulation to provide new understanding of how SFN influences this important target. We will test the idea that SFN treatment may regulate TG2 structure via mechanisms that involve direct covalent modification, and study the role of TG2 as a mediator of SFN action and a SFN treatment target in cultured ECS cells and tumors.

表皮鳞状细胞癌（SCC）是最常见的癌症之一。手术治疗 但复发和转移率接近10%。我们的科学前提是人类 表皮癌干细胞（ECS）在皮肤癌的早期形成，并且这些细胞是重要的癌症 预防目标。在这种情况下，一个重要的目标是识别和抑制关键蛋白质的活性， 提高和必需的ECS细胞存活。特别有趣的是，我们发现组织转氨酶 (TG2)，一种新兴的癌症干细胞存活调节因子，与非肿瘤干细胞相比， 干癌细胞更重要的是，TG 2敲低或用萝卜硫素（SFN）处理，这是一种有希望的治疗方法。 饮食来源的癌症预防剂，降低与ECS细胞存活减少相关的TG 2活性 另外的新研究表明，TG 2基因敲除可显著减少ECS细胞肿瘤的形成。我们也 提供了新的数据，表明SFN共价修饰TG 2，使其结构转变为开放式结构， 构象这些新的发现表明SFN处理将TG 2从封闭的（GTP结合， 信号传导）pro-ECS细胞存活形式转变为开放的无活性构象。我们的目标是描述这种独特的 监管提供了新的理解如何单频网影响这一重要目标。我们将检验 SFN处理可能通过涉及直接共价修饰的机制调节TG 2结构，并且研究表明， TG 2在培养的ECS细胞和肿瘤中作为SFN作用的介体和SFN治疗靶标的作用。