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（IGFs）发挥有效的增殖和抗肿瘤作用。 对结肠癌（CRC）细胞的凋亡作用，并可能在所有治疗过程中作为共致癌物发挥作用。 结直肠癌发生的阶段。膳食剂，如姜黄素，抑制CRC细胞的生长， 在疾病的癌前和癌后阶段抑制结肠癌发生。是的， 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， 姜黄素在生长因子如IGF-II和PG的存在下减弱;令人惊讶的是， IGF-II存在时的衰减显著高于PG存在时。 我们的拨款提案的主要假设是，姜黄素的抑制功效将由以下任一因素决定： 通过动物模型的循环生长因子谱或通过CRC细胞中的自分泌生长因子。解决 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效力。姜黄素的抑制作用 完整的结肠隐窝细胞，由过表达PG或IGF的转基因小鼠制备，或由 也将检查野生型小鼠。在目标2中，我们将研究饮食姜黄素的剂量依赖性效应 在过度表达PG或IGF-II的转基因小鼠中，无论是在 循环或局部在肠粘膜内。介导抗凋亡与 PG和IGF对CRC和肠上皮（IEC）细胞的增殖作用目前正在研究中。 在我们的实验室检查。姜黄素抑制生长因子作用的机制 IGFs和PG目前尚不清楚。在目标3中，我们将检查姜黄素对细胞增殖的影响。 磷酸化/去磷酸化的几种激酶/磷酸酶被激活响应PG或 IGF-II在同基因CRC和IEC细胞中。 上述实验将使我们首次了解姜黄素的相对有效性 在结肠癌发生的相关疾病的病因生长因子的存在下。 这些研究的结果有望有助于制定基于机制的策略， 使用姜黄素样试剂的CRC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.