Growth Factors, Curcumin and Colon Carcinogenesis

我们现在知道，前胃泌素 (PG) 和胰岛素样生长因子 (IGF) 具有有效的增殖和抗肿瘤作用。 对结肠癌 (CRC) 细胞具有凋亡作用，并可能在所有过程中充当共同致癌物 结直肠癌发生的各个阶段。姜黄素等膳食制剂可抑制结直肠癌细胞的生长， 在疾病的恶变前和恶变后阶段抑制结肠癌的发生。它是， 然而，尚不清楚姜黄素是否可以抑制自分泌和/或内分泌的生长因子效应 结肠癌发生过程中的 PG 和 IGF-II。我们的初步研究表明，抑制作用 姜黄素在生长因子（例如 IGF-II 和 PG）存在下会减弱；令人惊讶的程度 IGF-II 存在时的衰减明显高于 PG 存在时的衰减。因此， 我们的资助提案的主要假设是姜黄素的抑制功效将由以下任一因素决定： 动物模型的循环生长因子谱或结直肠癌细胞中的自分泌生长因子。致地址 根据这一假设，在目标 1 中，我们将开发表达 PG 或 IGF-II 的同基因细胞系，并检查 姜黄素对这些细胞的促凋亡和抗增殖功效。姜黄素的抑制作用 完整的结肠隐窝细胞，由过度表达 PG 或 IGF 的转基因小鼠制备，或由 野生型小鼠也将被检查。在目标 2 中，我们将研究膳食姜黄素的剂量依赖性影响 对抗过度表达 PG 或 IGF-II 的转基因小鼠结肠癌发生的所有阶段，无论是在 循环或局部肠粘膜内。介导抗凋亡与抗凋亡的细胞内途径 PG 和 IGF 对 CRC 和肠上皮 (IEC) 细胞的增殖作用目前正在研究 在我们的实验室进行了检查。姜黄素抑制生长因子作用的机制 IGF 和 PG 目前未知。在目标 3 中，我们将研究姜黄素对 几种激酶/磷酸酶的磷酸化/去磷酸化，这些激酶/磷酸酶响应 PG 或 同基因 CRC 和 IEC 细胞中的 IGF-II。 上述实验将使我们第一次了解到姜黄素的相对功效 在存在与疾病病因相关的生长因子的情况下对结肠癌发生的影响。 这些研究的结果预计将有助于制定基于机制的策略 使用姜黄素类药物的结直肠癌预防/治疗方案。

We now know that progastrins (PG) and insulin-like growth factors (IGFs) exert potent proliferative and anti- apoptotic effects on colon cancer (CRC) cells and can potentially function as co-carcinogens during all phases of colorectal carcinogenesis. Dietary agents, such as curcumin, inhibit the growth of CRC cells and inhibit colon carcinogenesis at both the pre-malignant and post-malignant stages of the disease. It is, however, not known if curcumin can inhibit the growth factor effects of autocrine and/or endocrine PG and IGF-II during colon carcinogenesis. Our preliminary studies suggest that the inhibitory effects of curcumin are attenuated in the presence of growth factors, such as IGF-II and PG; surprisingly the degree of attenuation was significantly higher in the presence of IGF-II than in the presence of PG. Therefore, the major hypothesis of our grant proposal is that the inhibitory efficacy of curcumin will be dictated by either the circulating growth factor profile of animal models or by the autocrine growth factors in CRC cells. To address this hypothesis, in Aim 1, we will develop isogenic cell lines that either express PG or IGF-II, and examine the pro-apoptotic and anti-proliferative potency of curcumin on these cells. Inhibitory effects of curcumin on intact colonic crypt cells, prepared from either transgenic mice over-expressing PG or IGFs or prepared from wild type mice, will also be examined. In Aim 2, we will examine dose-dependent effects of dietary curcumin against all phases of colon carcinogenesis in transgenic mice over-expressing PG or IGF-II, either in the circulation or locally within the intestinal mucosa. The intracellular pathways that mediate anti-apoptotic vs proliferative effects of PG and IGFs, on CRC and intestinal epithelial (IEC) cells, are being currently examined in our laboratory. The mechanisms by which curcumin inhibits the growth factor effects of IGFs and PG are unknown at the present time. In Aim 3 we will examine the effect of curcumin on the phosphorylation/dephosphorylation of several kinases/phosphatases that are activated in response to PG or IGF-II in isogenic CRC and IEC cells. The above experiments will allow us to learn for the first time the relative effectiveness of curcumin on colon carcinogenesis in the presence of growth factors relevant to the etiology of the disease. The results of these studies are expected to help in developing mechanism-based strategies for preventative/treatment protocols for CRCusing curcumin like agents.