Growth Factors, Curcumin and Colon Carcinogenesis

我们现在知道，孕激素(PG)和胰岛素样生长因子(IGFS)具有强大的增殖和抗肿瘤作用 凋亡对结肠癌(CRC)细胞的影响，并可能在急性淋巴细胞白血病(ALL)中起辅助致癌作用 结直肠癌发生的不同阶段。膳食剂，如姜黄素，抑制大肠癌细胞的生长和 在疾病的癌前和癌后阶段抑制结肠癌的发生。它是, 然而，尚不清楚姜黄素是否能抑制自分泌和/或内分泌的生长因子效应。 PG和IGF-II在结肠癌发生中的作用我们的初步研究表明， 姜黄素在IGF-II和PG等生长因子的存在下会减弱；令人惊讶的是， 在IGF-II存在的情况下，衰减显著高于PG存在的情况。因此， 我们拨款提案的主要假设是姜黄素的抑制效果将由以下两种因素之一决定 动物模型的循环生长因子图谱或结直肠癌细胞中的自分泌生长因子。致信地址 在这个假设中，在目标1中，我们将开发表达PG或IGF-II的等基因细胞系，并检查 姜黄素对这些细胞的促凋亡和抗增殖作用。姜黄素对小鼠肾小管上皮细胞的抑制作用 完整的结肠隐窝细胞，从过度表达PG或IGFS的转基因小鼠中制备，或从 野生型小鼠，也将接受检查。在目标2中，我们将检验饮食中姜黄素的剂量依赖效应。 在过表达PG或IGF-II的转基因小鼠中对抗结肠癌的所有阶段，无论是在 循环或局部在肠粘膜内。介导抗细胞凋亡的细胞内通路与 PG和IGFS对大肠癌和肠上皮(IEC)细胞的增殖作用目前正在研究中 在我们实验室进行了检验。姜黄素抑制血管内皮生长因子作用的机制 IGFS和PG目前尚不清楚。在目标3中，我们将研究姜黄素对血管内皮细胞生长的影响。 PG或PG激活的几种激酶/磷酸酶的磷酸化/去磷酸化 IGF-II在同基因的结直肠癌和IEC细胞中的表达。 上述实验将使我们第一次了解姜黄素的相对有效性 在存在与疾病病因相关的生长因子的情况下，结肠癌的发生。 这些研究的结果预计将有助于制定以机制为基础的战略 使用类姜黄素制剂的慢性肾衰的预防/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.