A novel sulforaphane cancer preventionmechanism

表皮鳞状细胞癌(SCC)是最常见的癌症之一。它是通过外科手术治疗的 切除，但复发和转移率接近10%。我们的科学前提是人类 表皮癌细胞(ECS)是皮肤癌早期形成的细胞，是重要的癌症细胞 预防目标。在这方面的一个重要目标是识别和抑制关键蛋白质的活性，这些蛋白质是 升高并对ECS细胞生存至关重要。特别有趣的是，我们发现组织转谷氨酰胺酶 一种新的肿瘤干细胞存活调节因子(TG2)在ECS细胞中比非ECS细胞中显著升高 干细胞癌细胞。更重要的是，TG2被击倒或用萝卜硫醚(SFN)治疗，这是一种有希望的 饮食衍生的癌症防御剂，降低TG2活性，这与ECS细胞存活率降低有关 更多的新研究表明，TG2基因敲除显著减少了ECS细胞肿瘤的形成。我们也 提供表明SFN共价修饰TG2以使其结构变为开放失活的新数据 构象。这些新的发现表明，SFN处理将TG2从封闭的(GTP结合， 信号)，支持ECS的细胞存活形成开放的非活性构象。我们的目标是将这一独特的 监管，以提供对SFN如何影响这一重要目标的新理解。我们将测试这一想法 SFN处理可能通过涉及直接共价修饰的机制调节TG2结构，并研究 TG2在培养的ECS细胞和肿瘤中作为SFN作用的中介和SFN治疗靶点的作用。

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.