Diindolylmethane:Inhibition of lung squamous cell carcinoma by targeting Akt.

描述(由申请人提供)： 本项目的主要目标是评估二吲哚甲烷(DIM)的有效性，DIM是一种来自十字花科蔬菜的活性化合物，通过靶向Akt信号通路来阻止支气管癌前病变向肺鳞状细胞癌(SCC)的恶性进展。初步研究表明，人的支气管细胞暴露于生理浓度的DIM可引起烟草致癌物转化的支气管细胞的抗增殖和凋亡效应，但对正常的支气管细胞没有影响。此外，我们观察到DIM抑制Akt信号通路中涉及的蛋白的激活/表达。在香烟烟雾转化的支气管细胞中过表达结构性激活的Akt可显著降低DIM的凋亡效应，表明DIM的生长抑制和凋亡活性是通过靶向Akt介导的。在目前的应用中，我们将把我们的研究扩展到肺鳞状细胞癌的小鼠模型，并评估DIM是否通过抑制Akt的激活而导致支气管癌前病变的消退。此外，我们将使用分子成像方法进行概念验证研究，以确认暗靶Akt的激活。假设：AKT激活在支气管癌前病变向肺鳞状细胞癌(SCC)的进展中起关键作用，DIM靶向Akt可以逆转这一过程。将使用N-亚硝基-三氯乙基脲(NTCU)诱导的小鼠肺鳞状细胞癌模型来验证这一假说。具体目的1：确定DIM是否抑制NTCU诱导的肺鳞状细胞癌，Akt信号通路是否是DIM化学预防作用的关键靶点。 特定目的2：利用基于荧光素酶互补的分子成像平台，检测磷酸化Akt靶向在体外对DIM诱导的肺癌抗增殖和凋亡作用以及在异种移植瘤模型中的作用。影响/意义：这项研究的结果可能为DIM ASA化学预防药物在肺癌高危人群中的临床试验提供机制基础和理论基础。

DESCRIPTION (provided by applicant): The main goal of this project is to assess the efficacy of diindolylmethane (DIM), a bioactive compound from cruciferous vegetables, to block the malignant progression of bronchial preneoplastic lesions to lung squamous cell carcinoma (SCC) by targeting the Akt signaling pathway. Preliminary studies showed that exposure of human bronchial cells to physiologically relevant concentrations of DIM caused antiproliferative and apoptotic effects in tobacco carcinogen-transformed bronchial cells but not in normal bronchial cells. Further, we observed that DIM inhibits activation/expression of proteins involved in the Akt signaling pathway. Over- expression of constitutively activated Akt in cigarette smoke-transformed bronchial cells markedly reduced the apoptotic effects of DIM, indicating that the growth inhibitory and apoptotic activities of DIM are mediated by targeting Akt. In the present application, we will extend our studies to a mouse model of lung SCC and assess if DIM causes regression of bronchial preneoplastic lesions by inhibiting Akt activation. Moreover, we will conduct, using a molecular imaging approach, proof-of-concept studies to confirm that DIM targets Akt activation. Hypothesis: Akt activation plays a critical role in the progression of bronchial preneoplastic lesions to lung squamous cell carcinoma (SCC) and targeting Akt by DIM reverses this process. N-nitroso-tris- chloroethylurea (NTCU)-induced mouse model of lung SCC will be used to test the hypothesis. Specific Aim 1: To determine if DIM-inhibits NTCU-induced lung SCC and whether the Akt signaling pathway is the critical target for the chemopreventive activities of DIM. Specific Aim 2: To examine, using luciferase complementation-based molecular imaging platform, the role of phospho-Akt targeting on DIM-induced antiproliferative and apoptotic effects in vitro and tumor growth in xenograft models of lung cancer. Impact/Significance: The results of this study could provide a mechanistic basis and rationale for clinical trials of DIM asa chemopreventive agent in populations that are at high risk to develop lung cancer.